Moleculer Basis Of Hemoglobinopathies Flashcards
What are Hemoglobinopathies
are a diverse group of inherited blood disorders that result from variations in the structure and/or synthesis of hemoglobin.
Hemoglobinopathies mainly include
1- thalassemias
2- sickle cell diseases (SCD)
If a Hemoglobinopathies disease is h eterogeneous
then multiple genes and alleles are causing it not only one ( Diverse]
What is the diffrence btw adult hemoglobin (HbA) and Fetal hemoglobin (HbF)
Normal adult hemoglobin (HbA) is a tetramer of two α chains and two β chains (α2β2). Fetal hemoglobin (HbF) is a is a tetramer of two α chains and two γ chains (α2γ2).
HbA2
What is it
is the third normal adult hemoglobin and it consists of 2 alpha and 2 delta subunits. This type constitutes only 2.5% of the
blood.
We have the fetal blood in our blood its about
2.5%
HBA in adult is about ….%
97
The globin genes are located in ….chromosomes
2
ch16 and 11
Why the alpha globin gene dosenot follow Mendalian inheritance
Bcs it has double the standered smount of genes —-> 4 genes
What is the importance of The locus control region (LCR
is the one reponsible for the switch between the transcription of the gamma globin chain gene and the b-globin chain gene.
- switch from embryonic to fetal to adult
LCR only found in … and …..
gamma globin chain gene and the b-globin chain gene
What is the importance of PYR complex
controls the switch of expression from
- gamma. To
- beta
Why alpha globin genes synthesis considered Constant
We have 2 copies of alpha and therefore 4 genes in our body. It is continuously expressed (Constant)
What happened to gamma globin gene synthesis
gamma globin dramatically decreases at birth
Notice how after birth, the synthesis of ….globin decreases and the …. globin production isincreased
- gamma
- beta
gamma globinisreplacedalmost completely by beta at the age of ….. weeks
50
Adult can have a traces of gamma
T
Thalassemia is
Reduction in either alpha or beta globin chain level is low but the structure is normal
Thalassemia can be classified as
- α-thalassemia: patients have a defective expression of α-globin genes
- β-thalassemia: patients have a defective expression of β-globin gene
…….patesints requiring lifelong blood transfusions with complications in multiple organ systems.
Thalassemia
(αα/αα) The deletion or inactivation of only one α-globin gene usually results in …..
insignificant hematologic findings
What is the result in insignificant hematologic findings
silent carriers)
- normal phenotype
- genotypes (α-/αα) or (αα/α-)
When 2 α-globin genes are deleted or inactivated, either on the same chromosome (αα/–) [southeast Asia] (cis) or on opposite
chromosomes (α-/α-) [African] (trans.), the affected person has
borderline anemia
What is borderline anemia
On the line between anemic or not
borderline anemia, characterized by….rbcs
microcytic
hypochromic
HbH disease caused by
The deletion of three a-globin [only one functional α-globin gene]
HbH disease: patients usually have anemia at ….. but ……
At birth
Not lethal
intrauterine anemia happened bcz of
Hb Bart’s hydrops fetalis syndrome
There is a difference between HbH disease and HbH hemoglobin as well as Hb Bart’s hemoglobin and Hb Bart’s hydrops fetalis syndrome.
T
Level of. Hb Bart’s, above 15% at birth is an indicative of HbH disease
T
Hb Bart’s (All gamma chains hemoglobin) can be present in HbH disease, but in small amounts that is not fatal like in Hb Bart’s Hydrops Fetalis syndrome
T
If you have 100% Hb barts then it will cause prenatal/postnatal death.
T
excess β-globin chains form β4 homotetramers [HbH Hb] leads to
severe form of α-thalassemia.
What is the diffrence btw HbH disease and HbH hemoglobin
- HbH Hb : homotetramer structure of 4 beta subunits
* HbH disease : Mutation in 3 genes when only one alpha is functional the other 3 are not working
HbH disease are not transfusion-dependent but may require transfusion support for
infections and other oxidative stresses.
The most common nondeletional form of HbH disease is
HbH Constant Spring
what is β-thalassemia
The aggregation/deposit of alpha globins lead to ineffective erythropoesis leading to premature death of RBCs.
Heinz bodies found in ….
hBH Erythrocyte
β-Thalassemia
β-thalassemia is caused by the reduction (β+) or absence (β0) of β globin chains synthesis.
There are three main types of β-thalassemia
- β-thalassemia carrier state or minor (clinically asymptomatic; heterozygous)
- β-thalassemia intermedia, (clinically and genotypically very heterogeneous)
- β-thalassemia major (severe transfusion-dependent anaemia)
The accurate identification of thalassemia intermedia versus thalassemia minor and major can be difficult if based on
clinical presentation alone
is the most accurate approach for distinguishing between the different types of β-Thalassemia.
Genetic analysis
Half of clinically severe thalassemia actually have the ….genotype
HbE/β- thalassemia genotype.
There were two siblings with HbE/β-thalassemia and one of them died immediately after birth while the other survived. If u looked at the genetic composition what will u find ?
The one who died had a mutated α chain because we said it becomes more severe when its combined with alpha mutation!
