Have you ever wondered how many cells are in your body? Well, for red blood cells alone, an average adult has over 25,000,000,000,000, making up 80% of the cells in the body. These red blood cells are made out of hemoglobin, an essential protein responsible for transporting oxygen around your body. However, in the case of an individual with thalassemia, a genetic anemia, their body cannot make enough healthy hemoglobin, causing their red blood cells to be less efficient, have shorter life spans, and not provide adequate oxygen to their organs.
Genetics
Before more is explained, we need to get into the nitty gritty aspects of DNA! Thalassemia is caused by a mutation in hemoglobin-producing genes. There are two types of thalassemia, alpha and beta, which correspond to the type of globin not being produced.
Alpha thalassemia is caused by the dysfunction of 2 nearly identical genes that contain the blueprint for alpha-globin on chromosome 16, called HBA1 and HBA2. Humans have 2 sets of each gene (4 in total).
Beta thalassemia is caused by the dysfunction of 1 gene that contains the instructions for beta-globin on chromosome 11, called the HBB gene, which humans have 2 copies of (2 genes in total). Interestingly, HBB is affected by over 100 types of mutations.
Levels of Severity
Now that we understand the role of genetics in thalassemia, we can learn how the severity of thalassemia is measured. The degrees of thalassemia are referred to by “trait”, “minor” (mild), “intermedia” (moderate), or “major” (severe). The more gene segments missing, the greater the severity of the disease.
Trait: an individual who lacks globin genes but displays no symptoms. Medical treatment is unrequired.
Major: an individual who displays severe symptoms. Requires consistent, lifelong medical assistance.
However, because alpha and beta thalassemia involve a different number of genes, there isn’t a one-size-fits-all diagnosis.
Alpha thalassemia concerns 4 genes:
An individual with 1 missing gene from chromosome 16 will likely become a ‘silent carrier’, who can pass on alpha thalassemia but does not display any symptoms.
An individual with 2 missing genes from chromosome 16 will likely present mild symptoms.
However, beta thalassemia concerns only 2 genes:
An individual missing 1 beta-thalassemia gene can display symptoms that range from asymptomatic to mild.
An individual missing 2 beta-thalassemia genes will display moderate to severe symptoms.
What Makes up a Red Blood Cell?
Now that you know what causes faulty globin, the next essential step is understanding what exactly a red blood cell (also known as an erythrocyte) 3 is.
Fun Fact: in hemoglobin, the “hemo” stands for heme, which contains iron and is the protein responsible for binding to oxygen. The “globin” acts as a protective structure for the heme.
An erythrocyte is primarily made up of 4 large proteins: 2 alpha-globin and 2 beta-globin. 1 heme protein rests in each globin, allowing a red blood cell to carry a total of 4 oxygen molecules.
However, in thalassemia patients, the DNA that codes for hemoglobin is incorrect, and globin is not properly made. For instance, in beta-thalassemia, an overabundance of unmatched alpha-globin chains follows a lack of beta-globin chains. These unmatched globin chains can result in a substance called hemichromes being precipitated on the surface of red blood cells once they enter the circulation, altering the cells’ structure, and thus, their efficiency, flexibility, and lifespan. As a consequence, a lack of healthy and efficient blood cells is produced. This all leads to oxygen not being effectively delivered around the body.
Symptoms
Since we’ve covered the basics of the confusing topic of what causes thalassemia, let’s move on to the symptoms and what causes them. External symptoms of thalassemia can include:
Fatigue and weakness
→ Caused by lack of oxygen.
Pale or yellowish skin
→ Caused by the build-up of the enzyme bilirubin, which is formed by the breakdown of hemoglobin.
Facial bone deformities
→ The bone marrow works harder to compensate for the lack of hemoglobin. This can weaken the bones, resulting in fractures and facial deformities.
Abdominal swelling
→ The spleen acts as a filter for blood, acting out quality control. The amount of malformed red blood cells builds up too rapidly, causing the spleen to work harder and enlarge.
Slow growth
→ Lack of oxygen results in less energy for your organs to use and grow.
Dark urine
→ Excess iron in the blood from broken down red blood cells is excreted through urine.
Prone to infection
→ High levels of iron in the blood can lower the amount of proteins relevant to the immune system.
Now you know the signs of thalassemia! However, I would not recommend attempting to diagnose your friends from these alone. Specific testing is required to confirm the genetic anemia (on top of being a trained professional).
Diagnosis
Some examples of methods to diagnose thalassemia are:
A complete blood count: A commonly done test that measures the size and quantity of erythrocytes and hemoglobin, amongst other cells, allowing for a diagnosis to be started. It can be done for any age. Signs that signify thalassemia are:
Lack of hemoglobin
Lack of red blood cells
Reduced size of red blood cells
A reticulocyte count:
This measures the amount of immature blood cells and if enough red blood cells are being produced in the bone marrow. This test can follow irregular results from a complete blood count test to narrow down the cause of a disease.
Iron studies:
This measures iron levels in blood for any age and can be used to determine if the cause of an anemic patient is a lack of hemoglobin (thalassemia) or an iron deficiency.
Hemoglobin electrophoresis:
This separates different types of hemoglobin, allowing for the detection of changes in hemoglobin A2 and F, which can be used to diagnose beta thalassemia but is not sensitive enough to properly diagnose alpha thalassemia. For detailed information on why hemoglobin electrophoresis can diagnose beta thalassemia but not alpha thalassemia, click here!
For a quick and easy read to learn about the different types of hemoglobin, click here!
A diagnosis cannot be made on little information, as doctors need to have a good understanding of what they are dealing with. After a sample has been collected from a patient, they are often sent to a lab to be analyzed. The image below is a flow chart of the methods and steps that can be taken when analyzing a disease relating to hemoglobin.
Treatments
With current technology, the most effective remedy for thalassemia is stem cell transplants from bone marrow. However, only 30% of patients are able to find a compatible donor (mostly siblings).
While there is no widespread cure, there are numerous treatments and medications that can improve an individual’s quality of life. These include:
Blood transfusions to provide healthy erythrocytes
Administered through an intravenous line with a needle
Frequent blood transfusions can cause excess iron in the bloodstream
Iron chelation therapy to remove excess iron
Available as a pill or vein injection
Depending on patient requirements and iron levels, EDTA (ethylenediaminetetraacetic acid) can be administered through a vein over the course of 30 minutes to a few hours. EDTA binds to metals in the bloodstream and can be secreted from the body through urine.
—> Excess iron can overload and damage organs. The heart in particular is highly susceptible to this.
Folic acid supplements
Available as a tablet
→ Folate is a crucial nutrient for erythrocyte growth, development, and proper function for red blood cells.
Gene Therapy Treatment
Gene therapy involves changing peoples’ own DNA to treat thalassemia. Several companies are currently working on this, one being the company Bluebird Bio, which developed Zynteglo, an FDA-approved gene therapy for beta-thalassemia in 2022. However, the price of Zynteglo is incredibly high, priced at 2.8 million dollars per patient, making it not available to the public majority.
In essence, stem cells from a thalassemia patient are extracted and brought to a lab, where the missing gene is added through a viral vector (modified virus). Chemotherapy is then used to remove the original faulty stem cells, and the modified stem cells are re-infused. These new genes can properly code for functional hemoglobin, averting the symptoms and reducing the need for blood transfusions. This is a more permanent and long-lasting treatment.
Inheritance and Population
Let’s consider another hypothetical: if your parents lacked the alpha or beta globin genes, how likely would you be to receive it? Thalassemia is dependent on autosomal recessive genes. This means gender does not affect one’s chances of inheriting thalassemia. Its recessive status allows for a child whose parents BOTH have thalassemia to not inherit it at all! Children’s severity of thalassemia depends on how many faulty or lack of globin-producing genes they inherit from their parents.
For instance, if both parents had mild beta thalassemia, their children would have:
25% chance of being unaffected
50% chance of also having mild thalassemia
25% chance of having moderate to severe thalassemia
However, keep in mind that the different number of genes in alpha and beta thalassemia means that inheritance can differ from each other. This is just the bare basics of genetics. Concerning 4 genes, alpha thalassemia has many possible offspring genotypes depending on parents, compared to beta-thalassemia. However, only a few examples are listed in the image.
Roughly 4.4 out of 10,000 babies are born with some form of thalassemia, and each year approximately 60,000 are born with symptomatic thalassemia.
Across the world:
Approximately 300,000,000 people have the thalassemia trait (carry the gene but lack symptoms)
Approximately 1,000,000 people have mild thalassemia (does not require medical assistance)
Over 100,000 people have moderate to severe thalassemia (requires medical assistance)
Conclusion
Thalassemia is a genetic anemia. Hopefully, that sticks with you once you finish this article! While this article was fairly information-heavy, much had to be simplified and packed into a neat box for you. Biology is incredibly complicated, and our knowledge only continues to grow with each new discovery. I encourage you to do your own research on the topics that interest you!
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