Hemoglobinopathies, Thalassemia.

Hemoglobinopathies
The hemoglobinopathies are inherited disorders of hemoglobin synthesis such as thalassemia, or
structure (sickle cell disorders) that are responsible for significant morbidity and mortality all
over the world.
They are seen mainly in individuals who originate from Africa, the middle east, the
Mediterranean, Asia and the far east.

Structure of hemoglobin
Hemoglobin is a multi-subunit globular protein, which has a quaternary structure – four globin
subunits are arranged in a tetrahedral structure. Each globular protein subunit contains a protein
chain which is associated with non-protein, prosthetic heme group. The alpha-helix structure of
the globin proteins creates a pocket which binds the heme group. Globin proteins are synthesized
by ribozymes in the cytosol. The Heme part is synthesized in the mitochondria. A charged iron
atom is held in the porphyrin ring by covalent binding of iron with four nitrogen atoms in the
same plane. These N atoms belong to the imidazole ring of the F8 histidine residue of each of the
four globin subunits. In hemoglobin, iron exists as Fe2+.

Thalassemia
Thalassemia, as the name might suggest- Thalassa in greek is sea and hema means blood, so it’s
a blood disorder related to the mediterranean sea, it is an autosomal recessive inherited blood
disorder characterized by less hemoglobin and fewer red blood cells in your body than normal.
Hemoglobin is the substance in the red blood cells that allows them to carry oxygen. The low
hemoglobin and fewer red blood cells of thalassemia may cause anemia, leaving the patient
fatigued.
In case of mild thalassemia, there is no need treatment. But in more severe form of the disorder,
patient may need regular blood transfusions.
Causes
Thalassemia is caused by mutations in the DNA of cells that make hemoglobin, the substance in
red blood cells that carries oxygen throughout the body. The mutations associated with
thalassemia are passed from parents to children recessively , it messes up the normal production
of hemoglobin and healthy red blood cells. This causes anemia. With anemia, the blood doesn't
have enough red blood cells to carry oxygen to the peripheral tissues leaving the patient fatigued.

Loci or locus

A locus is a fixed position on a chromosome, like the position of a gene. Each chromosome
carries many genes, human's estimated 'haploid' protein coding genes are 19,000–20,000, on the
23 different chromosomes. A variant of the similar DNA sequence located at a given locus is
named an allele. Gene mapping is the process of defining the locus for a particular biological
trait.

Pathogenesis
In Thalassemia the problem is in the globin units of the hemoglobin (2α and 2β ot tetramers). In
adults α hemoglobin is 95%, hemoglobin a 2 is 2.5%. if the defect is in a α chain or subunit, it is
called α Thalassemia. If the defect is in the β subunit it is called β Thalassemia.
A defect in either unit forms hemo tetramers, they will precipitate in the red blood cells because
they are water insoluble and then they will lead to ineffective erythropoiesis.
If globin chains are decreased then hemoglobin will be decreased, which result in anemia.

Alpha Thalassemia

In chromosome 16, can be diagnosed by genetic studies, types:

1. Alpha thalassemia trait: meaning 1 locus is deleted so it will be αα for one, and the
second will have α-, and it is a symptomatic. (A is 97%, A2 is 2% and F is 1% which is
normal).
2. Alpha thalassemia minor: here we have 2 loci deleted and it can be either α- α- or αα --. It
is a symptomatic, maybe the patient will have mild microcytic anemia, therefor low
MCV.
 3. Beta 4 tetramers: 3 loci deleted so beta chains will be unpaired, they are present in the red
blood cells not in the bone marrow, the symptoms are moderate to severe hemolytic
anemia, blood transfusion can be done till adulating.
4. Hemoglobin Bart’s: which is the worst, 4 loci deleted, so all of the alphas are deleted so
gammas form tetramers, and there will be no effective erythropoiesis due high affinity of
gammas to oxygen so it cannot deliver oxygen to tissues since it’s bound to gamma, the
symptoms are hydrops fetalis or death in the uterus.
HbH disease causes insignificant to moderate anemia, hepatosplenomegaly, and yellowing of the
eyes and skin. Some affected individuals also have bone changes such as overgrowth of the
upper jaw and an unusually noticeable forehead. The characteristics of HbH disease usually
appear in early childhood, and affected individuals typically live into adulthood.

Beta Thalassemia

Beta thalassemia is a blood disorder that decreases the production of hemoglobin. Hemoglobin is
the iron-containing protein in red blood cells that carries oxygen to cells all over the body.
Symptoms in general can be tired, pale, and sometimes murmur and angina (chest pain caused by
reduced blood flow to the heart). Very common in Italy and Greece. Happens in chromosome 11.
Types can be:
1. Mild anemia: due to splicing defects.
2. Severe anemia is due non sense mutation, stop codon therefore termination of protein
synthesis which is beta globin.
Is can also be:

 Heterozygous: minor- it has increase in the number of microcytic RBCs, idiopathic so

nobody knows why, so low hemoglobin, RBCs are high. It is asymptomatic or minor
anemia, causing decrease in hemoglobin A, increase in A2 and slight increase in
hemoglobin F, so hemoglobin electrophoresis in abnormal.
 Homozygous: can be either:
1. Major: due lack of beta alpha globin will precipitate forming hem tetramers that
will lead to 2 things, first in the bone marrow the red blood cells that contain the
hemo tetramers will die before being released because they are not healthy and
they won’t survive, or so called ineffective erythropoiesis.
Second, the tetramers will precipitate in RBCs so the macrophage in the spleen
will recognize these abnormal RBCs and destroys them causing hemolytic
anemia, the kidneys will increase erythropoietin production which will lead to
erythroid hyperplasia, erythroid is the cell line that produces RBCs, and
hyperplasia means increase in the number of cells. But due the massive need of
RBCs the spleen and the liver and the reticulo-endothelial organs will help which
 is called extra-medullary hematopoiesis and start forming new red blood cells.
Due to the hyper activity of the organs they will enlarge “hepatosplenomegaly”.
The medullary cavity in the skull and the bones will enlarge showing “hair on
end” appearance on the X-ray, the maxillary bone will enlarge whch leads to
“chipmunk facies”. The patients will become dependent on blood transfusions.
The blood contains iron which will lead to iron overload hemosiderosis and
secondary hemochromatosis. Due hemoglobin degradation we will have
unconjugated bilirubin or hyperbilirubinemia and jaundice.
2. Intermedia: it is an intermediate form, there is a co-inheritance with alpha
thalassemia trait. We also have minor qualitative defect in beta globin meaning
less hemo tetramers so there is less hemolysis than the major type. Hemoglobin F
will increase due lack of betas, therefore gamma chains will form when you have
both alpha and gamma resulting hemoglobin F the fetal form.

Sources:

1. https://ghr.nlm.nih.gov/condition/beta-thalassemia
2. https://ghr.nlm.nih.gov/condition/alpha-thalassemia
3. https://www.mayoclinic.org/diseases-conditions/thalassemia/symptoms-
causes/syc-20354995
4. https://www.youtube.com/watch?v=HYZMFZbNbPQ
5. https://medlineplus.gov/ency/article/000587.htm
6. https://www.cdc.gov/ncbddd/thalassemia/facts.html
7. https://www.medicalnewstoday.com/articles/263489.php
8. https://kidshealth.org/en/parents/beta-thalassemia.html

By:

 SALI KHURI 1801944

 NASSIM SAID 1802142