Alpha-thalassemia

Definitions & Key takeaways

Alpha-thalassemia is an inherited blood disorder in which there is insufficient production of alpha globin chains of hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen from the lungs to all parts of the body. Symptoms will vary depending on the extent of the deficiency of the globin chains. Some people with alpha-thalassemia do not have symptoms, while others experience mild to moderate anemia.

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Introduction0:00–0:15

Alpha thalassemia is a genetic disorder where there's a deficiency in the production of the alpha globin chains of hemoglobin, which is the oxygen carrying protein in red blood cells.
Normally, hemoglobin is made up of four globin chains. Each bound to a heme group.

Physiology0:15–1:06

There are four major types of globin chains, alpha, beta gamma and delta. These four globin chains combine in different ways to give rise to different kinds of hemoglobin.
First, there's hemoglobin F or HB F where F stands for fetal hemoglobin. And it's made of two alpha globin and two gamma globin chains.
Hemoglobin A or HBA is the major form of adult hemoglobin. And it's made of two alpha globin and two beta globin chains.
Finally, hemoglobin A two or HBA, two amounts for a small fraction of adult hemoglobin in the blood. And it's made of two alpha globin and two delta globin chains.
Alpha chain synthesis is controlled by four alpha genes, two on each copy of chromosome 16. And alpha thalassemia is caused by mutations in the alpha genes.

Causes1:06–1:31

Most commonly a gene deletion. The mutations are inherited in an autosomal recessive pattern, which means that you need mutated genes from both parents to get the disease.
If a person has one defective alpha gene, they're called a silent carrier because they don't have symptoms, but they can still pass the gene on to their Children.

Pathology1:31–3:56

If a person has two defective alpha genes, the person has alpha thalassemia minor which causes mild symptoms. This can either be caused by a cyst deletion where mutated genes are on the same chromosome or a trans deletion.
When the mutated genes are on two different chromosomes, cyst deletion variants are more prevalent in Asian populations.
Whereas trans deletion variants are more prevalent in African populations. If there are three defective alpha genes, there is moderate disease called hemoglobin h or HBH disease.
This is caused by excess beta chains which clump together within developing red blood cells to form tetramer or beta four and give rise to a form of hemoglobin called hemoglobin.
H HBH molecules cause hypoxia in two ways. First, they damage the red blood cell membrane resulting in intramedullary hemolysis or red blood cell breakdown in the bone marrow or extravascular hemolysis when red blood cells are destroyed by macrophages in the spleen.
Second, hbh has a very high affinity for oxygen and doesn't release oxygen to the tissues. And a consequence of hypoxia is that it signals the bone marrow as well as extramedullary tissues like the liver and spleen to increase production of red blood cells.
This can cause the bones that contain bone marrow as well as the liver and the spleen to enlarge. Finally, if all four alpha genes are deleted, it results in HB Bart's hydrops, fetalis.
The problem here begins during fetal life where gamma chains form tetramer in the absence of alpha chains called HB Barts gamma four.
And it has super duper high affinity for oxygen about 100 times that of normal hemoglobin. So the tissues get no oxygen resulting in severe hypoxia, severe hypoxia leads to high output cardiac failure and massive hepatosplenomegaly resulting in edema all over the body called hydrops, fetalis.
This condition is incompatible with life and without treatment, the fetus usually dies in utero or soon after birth. The initial symptoms of minor and moderate alpha thalassemia are due to anemia which include pallor shortness of breath and easy fatiguability.

Symptoms3:56–4:13

There can also be skeletal deformities and hepatosplenomegaly diagnosis starts with a routine blood test that shows low hemoglobin levels decreased mean corpuscular volume or MCV and low mean corpuscular hemoglobin or MC H.

Diagnosis4:13–5:16

The peripheral blood smear shows microcytic or small and hypochromic or pale red blood cells. There are also target cells which are small red blood cells that look like bulls eyes due to scrunching up of excess cell membrane with moderate alpha thalassemia.
There may be golf ball like red blood cells due to precipitated Hbh molecules, hemoglobin, electrophoresis can be done to see which hemoglobin types are present.
For example, HBH will be seen as an extra band ahead of H ba on electrophoresis. Finally, the diagnosis is confirmed by genetic testing to look for hemoglobin gene mutations.
This can also be done prenatally by testing fetal DNA obtained through either chorionic villus sampling or amniocentesis.
Usually patients with mild alpha thalassemia don't need treatment. While patients with severe thalassemia are treated with blood transfusions based on the requirement for transfusion or not all alpha thalassemia subtypes can be grouped into two clinically relevant categories.

Treatment5:16–5:46

These are transfusion dependent thalassemia and non transfusion dependent transfusion dependent thalassemias involve all the subtypes in which recurrent blood transfusions are needed for survival like surviving HB Barts, hydrops, fetalis and severe forms of HB H disease.

Summary5:46–7:02

On the other hand, nontransfusion dependent thalassemias refers to the thalassemias that do not require regular blood transfusions for survival such as alpha thalassemia intermedia involving most HB H disease cases.
It is important to note that for the prevention of transfusion related iron overload iron chelating agents may be given to trap some excess iron and sweep it away through feces or urine.
When diagnosed prenatally, hb Barts, hydrops, fetalis can be treated with intrauterine transfusions and later followed up with bone marrow transplantation.
All right, as a quick recap alpha thalassemia is an autosomal recessive disorder caused by deletion of alpha globin genes.
On chromosome 16 single gene defect results in a silent carrier state which is asymptomatic. Two defective genes results in alpha thalassemia minor which causes mild anemia.
Three defective genes causes hbh disease, which causes severe anemia with hepatosplenomegaly. And four defective genes results in hb Barts hydrops, fetalis, which is incompatible with life.
And without treatment, the fetus usually dies in utero or soon after birth.