20.04.10 Haemoglobinopathies - sickle cell, thalassemia's Flashcards
What are haemoglobinopathies
Disorders caused by pathogenic sequence variants which affect the genes that synthesize globin chains of haemoglobin.
What is haemoglobin
Iron containing oxygen-transport metalloprotein in the red blood cells of all vertebrates.
Normal red blood cells contain 3 types of haemoglobin
- HbA (86-98%) α2beta2
- HbA2 (1.5-3.2%). α2delta2
- HbF (0.5-0.8%). α2gamma2
What encodes the 2 α globin genes
- HBA1 and HBA2 (chr 16)
- Different expression levels: α2:α1 is 3:1
- Expression is controlled by locus control region (LCR)
- earliest embryonic forms are closest to LCR, so HBA2 is closer to LCR
What is alpha-thalassemia
- Includes all conditions with a deficit in alpha globin chain production
- Most prevalent in regions where malaria is endemic as it confers some protection.
- Frequency of alpha-thalassemia alleles in Mediterranean basin= 5-10%, West Africa= 20-30%, Saudi Arabia, Papua New guinea, Thailand and India= as high as 60-80%
What is the most common cause of α thalassemia
- Deletion of 1 or both alpha genes (90% cases)
- 10% cases caused by point mutations in HBA2 (α+α) or HBA1 (αα+), from promoter to polyadenylation site
- α0 indicates no HBA expression from the allele
- α+ indicates some α-globin is produced from affected allele.
Is there are correlation between phenotype and degree of α-globin chain deficiency
Yes
What causes the majority of deletion type α-thalassemia
Reciprocal recombination between the two chromosome 16. Due to the high degree of sequence homology within α globin gene cluster.
What produces -α3.7
- Rightward crossover due to mispairing of Z boxes during meiosis.
- Fusion protein has 3 α globin genes, reciprocal is an allele with 1 α globin gene
What produces -α4.2
- Leftward crossover due to mispairing of X boxes during meiosis.
- Fusion protein has 3 α globin genes, reciprocal is an allele with 1 α globin gene
When are α globin genes most active
Early in fetal life. Therefore alpha-thalassemia is an issue for an unborn child
What are the 4 α -thalassemia syndromes
- Hemoglobin Bart hydrops fetalis (Hb Bart) syndrome. Most severe
- Hemoglobin H (HbH) disease.
- α-thalassemia trait.
- α-thalassemia silent carrier.
What is Hemoglobin Bart hydrops fetalis
- Most severe α -thalassemia syndrome.
- Due to loss of all 4 α-globin genes
- Usually results in still birth or neonatal death. Only HbH formed.
What is Hemoglobin H (HbH) disease
- Loss of 3 alpha-globin genes.
- Body produces HbH (beta-globin tetramers instead to compensate but unstable and forms Heinz bodies (red blood cell inclusions)
- Patients also have microcytic anaemia, moderate extravascular hemolysis, splenomegaly
What is α-thalassemia trait
Loss of 2 alpha globin genes either in cis (–/αα, α0 carrier) or in trans (-α/-α). Asymptomatic but may have microcytic anaemia. Important in antenatal setting to know which to assess risk to unborn child.