Lecture 33 Hemoglobinopathies Flashcards
On what chromosome can you find alpha-like globing genes ?
chromosome 16
On what chromosome can you find beta-like globing genes?
chromosome 11
how many alpha globin genes in a normal individual ?
4
how many beta globin genes in a normal individual?
2
a boy has a glutamate to valine change on the beta globing protein, what disease is this?
Sickle cell disease
At what point does a child have gamma (V) globulin gene expression?
from conception and is repressed after birth
At what point does a human have beta globulin gene?
after 6 months of birth
fetal hemoglobin has what kinds of hemoglobin?
HBf
2alpha 2gamma chains
Adults have what kind of hemoglobin?
HbA and and HbA2
HBA= 2alpha 2 beta (90-95%)
hemoglobin A2= 2 alpha 2 delta (3-5%)
What is the difference between hemoglobinopathy and thalassemia?
hemoglobinopathy= qualitative change; mutation in nucleotide sequence of globing chain
Thalassemia= Quantitative change decreased or absent globing chain synthesis
What occurs with hemoglobin S?
it is a single point mutation in beta globing gene HBB on the 6th codon. Glutamic acid is substituted by Valine at position 6 of beta globin chain.
how would HBS and HBA behave in an electrophoresis?
well HbS has a glutamic acid to valine change, therefore, it will move slower than HbA. the anode is + so it will be more attracted to the original glutamic acid
What kind of inhertance causes sickle cell disease?
homozygous inheritance of HbSS. There is no production of HbA
Therefore= autosomal recessive trait
you get painful episodes sickle cell crisis and hemolytic anemia
What are sticky patches?
sticky patches are found on sites were oxygen is supposed to bind on HbS, there is a lot of polymerization/sickling on these cells. they stick together in blood vessels causing pain
How do you repress fetal globin ( gamma) transcription after birth?
methylation of CpG
What drugs increase fetal globin ( gamma) after birth?
most importantly
hydroxyurea, and butyrate compounds ( inhibit histone deacetylation) this increases HbF
5-acytidine (decitabine;demethylating ages)
epigenetic gene regulation is changed and histone acetylaition is on, now there is expression of HbF (gamma globulin) there is derepression of the gene. This is how you treat sickle cell anemia because the blood is less likely to sickle HBs polymerization is inhibited
What does HbAS mean?
you are heterozygous for sickle cell trait. you have 1 normal B globin and 1 Bs globin gene= produce normal and abnormal= these people develop sickling crisis at low oxygen saturation
what countries have a high carrier frequency for sickle cell trait?
Africa, mediterranean basin, Middle East, and India
what is the survival advantage of sickle cell heterozygosity?
against falciparum malaria
What characterizes hemoglobin C (HbC)?
point mutation at 6th codon of beta globin gene resulting in missense mutation glutamine to lysine.
this one moves slowest to the anode because lysine is + and so is the anode
these people have milk hemolysis
HbC has lower solubility than HbA and crystalizes in RBCs
What characterizes HbSC?
they have different mutations of beta globin gene. One beta globin gene has S mutation and the other has C mutation.
they have sickling episodes similar to sickle cell disease
What is thalassemia?
reduced globin chain synthesis
what is is alpha thalassemia?
reduced alpha chain synthesis
what is beta thalassemia?
reduced beta chain synthesis
thalassemia has a selective advantage to what?
malaria
What characterizes alpha thalassemia? what is the embryonic explanation for it?
- reduced alpha globin chain synthesis
- relative excess beta globin or gamma globin chains
- deletion of entire alpha globin gene
- unequal cross-over during homologous recombination
- 2 alpha globin genes: 4 copies of alpha globin genes (HBA1 and HBA2)
- complex inheritance
what occurs if you have 3 working alpha globin genes and one is not working?
you are a silent carrier of alpha thalassemia
what occurs if you lose two genes of alpha globin?
then you have mild anemia
what occurs if you lose three genes of alpha globin?
beta4 tetramers HBh disease, moderate hemolytic anemia
what occurs if you lose all alpha globin genes ?
it is lethal, hydrops fetalis/ Hb bart
losing two genes of aloha globin and having the cis confirmation versus the trans coformation is _______ severe.
having the cis conformation is more severe..
If both parents have this cis form then the child won’t have working hemoglobins.
cis= one chromosome lacks copies and the other is normal trans= each chromosome has one bad copy
what is the most severe form of alpha thalessemia?
Hb bart/ hydrops fetalis
what is aggregated in Hb Bart?
gamma4 tetramers
all 4 alpha globin genes are deleted
there is no detectable HbF or HbA
symptoms include: edema, ascites, pleural and pericardial effusions, and severe hypochromic anemia, stillbirth or death in neonatal period
a patient has 3 deletions of alpha globin, has mild to moderate microcytic hypochromic hemolytic anemia and hepatospleenomegaly. what disease do they have ?
HBH disease
this is an aggregation of beta4 tetramers there is deficieny of alpha globin gene
Hba is low or low normal
what characterizes Beta thalassemia?
autosomal recessive inheritance
different mutations of beta globin genes ( allelic heterogeneity)
absent or reduced sythensis of beta globin chains of Hb. Excessive alpha globin chains precipitate and severe hemolytic anemia
excess alpha globin chains bind to RBC membranes causing membrane damage.
Form toxic aggregates resulting in hemolysis
HBB is what kind of heterozygosity ?
beta thalesemia and compound heterozygosity.
what does beta + mean in beta thalassemia?
it is a beta globin mutation that has reduced gene expression
what does beta 0 mean in beta thalassemia?
complete suppression of gene expression
what disorder is characterized by “ Cooley’s anemia or mediterranean anemia?
Beta thalassemia major
-these people are either homozygotes or compound heterozygotes for Beta 0 or Beta + genes
- two severe mutations
- very low or absent HbA levels- absent or very little Beta globin synthesis
- high HbA2 and HbF levels ( compensatory)
what does the disorder beta thalassemia intermedia characterize as?
- homozygotes, compound heterozygotes ( different beta + mutations)
- One severe mutation, second mutation less severe or two less severe mutations
- Low HbA levels- some beta globin synthesis
what characterizes beta thalassemia minor?
carrier/ trait/ or heterozygote.
heterozygote: one mutant and one normal B globin gene
- almost normal HbA levels
If there are different mutations in the same Beta globin gene than what is that called?
allelic heterogeneity
Frontal bossing and malar prominence, and hair on end indicate what?
extramedullary erythropoiesis
more common in beta thalasemia but can be seen in alpha too
bone marrow tries to compensate and expands to perform erythropoiesis and leads to bone deformity and fractures; erythropoiesis in flat bones is stimulated
at what age does homozygous be thalassemia present ?
this is thalassemia major and it presents at about 6 months to 2 years as gamma globin is switched off from Hf.
How do you manage the anemia that comes with beta thalassemia?
Regular transfusions correct anemia and suppress erythropoiesis, but lead to iron deposition
- iron chelation and dietary control to manage complications
bone marrow transplantation from HLA identical siblings
what is the inheritance of hemophilia A and B
x linked recessive, genes for factor 8 and 9 on X chromosome
hemophilia A is a deficiency of what factor?
intrinsic factor 8
Hemophilia B is a deficiency of what factor?
intrinisic factor 9
What are the clinical presentations of Hemophilia A and B
hemorrhage into joints and muscles, easy bruising, and prolonged bleeding from wounds
what is the genetic error that occurs in hemophilia A?
intron inversion that disrupts factor 8 (40%)
and deletions insertion and point mutations (50-60%)
has allelic heterogeneity
what is factor 9 genetic error?
point mutations and deletions
what occurs with intron inversion of factor 8?
- severe hemophilia A
- repetitive non-coding sequence (int22h)
- misalignment during homologous recombination and part of factor 8 gene is lost
- completely disrupted factor 8 gene ( exons 1 to 22) are displaced towards the telomere and oriented opposite to -their normal orientation. A contiguous factor 8 gene transcript from exon 1 to 26 is no longer possible and severe hemophilia results.
a carrier mother of hemophilia has what chance of passing it to the daughter?
50%
affected fathers of hemophilia have what chance of passing down an affected gene to daughters?
100% all daughters are obligate carriers. and all sons are normal
How can a female present with symptoms of hemophilia?
manifesting heterozygote/ lionization/ x inactivation
how do you treat hemophilia?
recombinant factor 8 or 9 replacement therapy. you receive clothing factor from pooled blood.. people used to contract HIV this way because they didn’t check blood before
