Post on 09-Oct-2020
Dr.Abdolreza Afrasiabi
Thalassemia & Heamophilia Genetic Reaserch Center
Shiraz Medical University
Hemoglobin tetramer
http://en.wikipedia.org/wiki/Image:Hemoglobin.jpg
Hemoglobin Structure %
A1 α2 β2 94-97%
A2 α2 δ2 2.5%
A1C α2 (β-N-glucose) 3%
F α2 γ2
There are 3 main categories of inherited Hemoglobin abnormalities:
Structural or qualitative: Genetic mutation involving amino acid deletions or substitution .(Hemoglobinopathy).
Quantitative: Production of one or more globin chains is
reduced or absent (Thalassemia).(HPFH): Hereditary persistence of Fetal Hemoglobin.
Complete or partial failure of γ globin to switch to βglobin.
Heterogenous group of disorders due to an imbalance of α and β globin chain synthesis
α thalssemia: α-globin chain production decreased
β thalassemia: β globin chain production decreased
Quantitative deficiency:
0 thalassemia: No β -globin chain is made
β + thalassemia: decreased b-globin chain is made
Beta () thalassemia:
- The disease manifests itself when the switch from to chain synthesis occurs several months after birth
- There may be a compensatory increase in and chain synthesis resulting in increased levels of Hb-F and A2.
- The genetic background of thalassemia is heterogenous and may be roughly divided into two types:
0 in which there is complete absence of chain production. This is common in the Mediterranean.
+ in which there is a partial block in chain synthesis. At least three different mutant genes are involved:
+1 – 10% of normal chain synthesis occurs
+2 – 50% of normal chain synthesis occurs
+3 - > 50% of normal chain synthesis occurs
Lab findings include:
Prepheral Smear
- hypochromic, microcytic anemia
- marked anisocytosis and poikilocytosis
- schistocytes, ovalocytes, and target cells
- basophilic stippling from chain precipitation
- increased reticulocytes and nucleated RBCs
chronic hemolysis leads to increased bilirubin and gallstones
hemoglobin electrophoresis shows increased Hb-F, variable
amounts of Hb A2, and no to very little A.
β-Thalassemia minor
Test to identify HbS.
HbS is relatively insoluble compared to other Hemoglobins.
Add reducing agent
HbS will precipitate forming and opaque solution compared with the clear pink solution seen in HbS is not present.
Solubility test (Sickledex):
Alpha () thalassemia
The disease is manifested immediately at birth
There are normally four alpha chains, so there is a great
variety in the severity of the disease.
At birth there are excess chains and later there are excess
chains. These form stable, nonfunctional tetramers that
precipitate as the RBCs age leading to decreased RBC
survival.
The disease is usually due to deletions of the gene and
occasionally to a functionally abnormal gene.
I. Silent carrier state
II. Alpha thalassemia trait
III. Hemoglobin H –disease
IV. Hemoglobin H –constant spring
V. Homozygous constant spring
VI. Hydrops fetalis
Lack of alpha protein is so small
Generally causes no health problems
Diagnosed when individuals has a child with Hb-H
or alpha thalassemia trait
Hb constant spring is an unusual form of it and
caused by mutation of alpha-globin with no health
problems
Reduced MCV and MCH with normal Hb A2 in
lab data
Physicians often mistake with iron deficiency
anemia
Created by the remaining beta globin
Lack of alpha protein is great enough to cause sever
anemia and health problems such as an enlarged
spleen, bone deformities, and fatigue
One parent is constant spring carrier and other
carrier of alpha thalassemia trait
Affected individual have a more sever anemia and
suffer more frequently from enlargement of the
spleen and viral infections
When two constant spring carriers pass their genes
on to their child .
The condition is less sever than Hb H-constant
spring and more similar to Hb-H disease.
There are no alpha gene in the individual’s DNA
Gamma globins produced by the fetus to form an abnormal Hb called Hb Barts.
Most individuals die before or shortly after birth
Co inheritance with heterozygous beta-thal and alpha-thal in particualr -alpha/-alpha genotype may be normalize MCV and MCH while Hb A2 levels remain elevated .
Interaction of delta-thal and beta-thal trait may reduce Hb A2 to borderline or normal level while MCV and MCH are reduced. phenotype of delta-beta-thal is similar to alpha but alpha/beta globin chain synthesis is 1.2 in delta-beta carrier.
1) Megaloblastic Anemia due to B12/Folic Acid deficiency
2) Liver disease (Lipid Metabolism)
3) Unstable Hb , Sickle Trait , S/B, S/a
4)hyper Thyroedism
5) Viral Treatment in Acquired immune deficiency HIV
6) Combined a/B with Normal index
1) Delta Beta Thalassemia (Hetero/Homo)
2)Hb H disease
3) Unstable Hb , Sickle Trait , S/B, S/a
5) Iron deficiency
6)Hb D
1) Hb A´2 –Hb G in S window in HPLC or Capillary System
a) Mutation in Delta gene (16 Gly Arg)
With increased Hb F
Parental Options
Procurement
removal of AF transabdominally with US* at 14-16 weeks
gestation determined via last menstrual period (LMP)
*Ultrasound (US):
locates the placenta (anterior or fundal in 70%)
assess amount of AF
date pregnancy via BPD, femur length, chest size
locate fetus
assess anatomy (brain, spinal cord, stomach, kidneys, HR)
Procurement (cont)
removal of 10-20 cc fluid which contains amniocytes
and fluid
use 20-21 gauge spinal needle, strict asepsis w/ or w/o
local anesthetic
AF is produced by the fetus
amniocytes are fetal in origin: skin, amnion, eyes, GU
tract, GIT, respiratory system
Risks1-3% overall for experienced docFetus:
infection (
Problems/complications
cannot do AFP for NTD; must do MSAFP at 15+ weeks
mosaicism
Rh
limb defects
Greatest advantage
TIME