What Causes Sickle Cell Anemia?
Medically reviewed by Steffini Stalos, DO
Sickle cell anemia is a genetically inherited disorder of the hemoglobin in red blood cells (RBC). Hemoglobin is the protein in RBCs that transports oxygen throughout the body.
In people whose hemoglobin and RBCs function properly, the red blood cells are flexible and round and can move through small blood vessels without breaking. In those with sickle cell disease, the RBCs become stiff and form the shape of a C or a sickle. These sickle-shaped cells can get stuck in smaller blood vessels and lead to problems.
This article will discuss the genetic causes of sickle cell anemia, how it's inherited, how often it occurs, diagnosis, and treatment.
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What Causes Sickle Cell Anemia?
Sickle cell anemia is caused by an abnormal HBB gene. The abnormal hemoglobin produced by this gene mutation (hemoglobin S) can cause the red blood cells to form into an abnormal sickle shape.
A normal RBC lives for about 120 days before the cell dies. The bone marrow continues to produce RBCs to make up for the loss.
In sickle cell anemia, the sickle-shaped RBCs live for approximately 10 to 20 days. This quick cell death decreases the number of RBCs in the body as the bone marrow isn’t able to keep up. This results in anemia (a low number of healthy red blood cells).
In addition to anemia, other problems can develop because of sickled cells. These cells can get stuck in the blood vessels, clogging them up and resulting in significant pain and other complications.
How Is Sickle Cell Anemia Inherited?
Sickle cell anemia is caused by a mutation in the HBB gene responsible for producing the beta-subunit of hemoglobin, inherited from one or both parents. There can be multiple mutations in the HBB gene, which, when inherited, can cause a different severity of the disease.
The normal gene is called hemoglobin A gene. The abnormal sickle cell gene is called the hemoglobin S gene.
In order to be born with the most severe form of sickle cell anemia, two copies of the abnormal HBB hemoglobin S gene must be inherited (one from each parent). If you inherit one copy of hemoglobin S and one of another type of defective hemoglobin, you may also show signs of sickle cell anemia.
This inheritance pattern is called autosomal recessive. "Autosomal" means that the gene is not on the X or Y chromosomes, so all sexes have an equal chance of inheriting it. "Recessive" means the person has two copies of the defective gene in order to display the condition.
If only one copy of the hemoglobin S gene is inherited, and the person inherits a normal hemoglobin A gene from the other parent, this individual has what's called sickle cell trait. People with sickle cell trait usually don't develop the symptoms of sickle cell anemia. However, they will be able to pass the hemoglobin S gene to their children.
You can inherit sickle cell trait if one of your parents has sickle cell anemia (two defective hemoglobin genes) or has sickle cell trait.
If both your parents have sickle cell trait, meaning they both carry only one copy of the hemoglobin S gene, you have a 25% chance of having two normal hemoglobin A genes. If you are born with two hemoglobin A genes, you'll produce normal hemoglobin and have neither sickle cell trait nor sickle cell anemia.
The parents who both have sickle cell trait have a 25% chance of their child inheriting two S genes and being born with sickle cell anemia. These parents also have a 50% chance of their child being born with only one hemoglobin S gene and having sickle cell trait.
Child's condition | Risk for each child if both parents have sickle cell trait |
Sickle cell anemia | 25% |
Sickle cell trait | 50% |
Typical hemoglobin | 25% |
Other genetic mutations in the HBB gene do not cause such severe disease, such as hemoglobin C, D, or O.
Frequency
Sickle cell anemia is most often found in people of African descent, but can also be found in people whose ancestors were from:
Mediterranean countries, such as Greece, Turkey, and Italy
India
Saudi Arabia
South America
Central America
Caribbean
Sickle Cell Numbers
It is estimated that 1 in 365 Black Americans are born with sickle cell disease, as are 1 in 16,300 Hispanic Americans. Approximately 100,000 Americans have sickle cell disease. About 1 in 13 Black Americans carry the sickle cell trait.
Diagnosis
Sickle cell anemia is often diagnosed in a newborn, as part of the blood work done in newborn screening tests. This testing is routine for newborns in every U.S. state and the District of Columbia. It detects both sickle cell anemia and sickle cell trait.
An adult can be evaluated for sickle cell anemia through a test called hemoglobin electrophoresis. This test evaluates the types of hemoglobin in the blood by sending an electric current through the blood sample, which separates the types of hemoglobin present. This can determine if abnormal hemoglobin, such as hemoglobin S, is present.
Symptoms of Sickle Cell Anemia
Symptoms of sickle cell anemia can include the following:
Fatigue and feeling tired
Jaundice (a yellowing of the skin and eyes)
Swelling of the hands and feet
Fever
Chest pain, cough, shortness of breath
Priapism (prolonged erection lasting four hours or more)
Stroke-like symptoms
Treatment
The only potential cure for sickle cell anemia is a bone marrow transplant, though this is mostly reserved for people who are critically ill with the disease. There are other treatment options for the disease and its symptoms.
An oral medication called Oxbryta (voxelotor) is available, which works by preventing the red blood cells from forming into the sickle shape. This medication can also increase the lifespan of the RBC, which improves anemia.
Other medications, including Adakveo (crizanlizumab-tmca) and Siklos (hydroxyurea), can be used to reduce the episodes of sickle cell crises (painful episodes or other severe complications).
Gene-editing therapies include Casgevy (exagamglogene autotemcel) and Lyfgenia (lovotibeglogene autotemcel).
Blood transfusions may be needed when people are severely anemic or when they are going to have surgery or another procedure when the risk of bleeding is high.
Takeaway
In 2023, The Food and Drug Administration (FDA) approved Casgevy and Lyfgenia for the treatment of sickle cell disease in people 12 years and older who have recurrent vaso-occlusive crises. These treatments work by removing cells from the bone marrow, modifying them, and returning them modified cells back to the patient. The modified cells are resistant to sickling, which reduces symptoms of sickle cell disease. These treatments are not a cure for sickle cell anemia but are designed to be a one-time treatment to alleviate symptoms for a lifetime.
Summary
Sickle cell anemia is a hereditary genetic disorder in which a mutated gene produces abnormal hemoglobin. The hemoglobin forms rigid strands that cause the normally round red blood cells to form a sickle shape.
This shortens the cells' life span, leading to anemia. Because of their shape, the sickle cells also have difficulty moving through small blood vessels, which can result in complications such as severe pain and damage to organs and tissues.
To have sickle cell disease, a person must inherit the defective hemoglobin S gene from both parents, or hemoglobin S from one parent and another abnormal hemoglobin gene from the other parent. These genetic mutations are most common in Americans of African descent.
Sickle cell anemia is diagnosed through a blood test called hemoglobin electrophoresis. Treatment is mostly supportive, with blood transfusions and medications to help prevent complications. A bone marrow transplant is the only chance for a cure.
Frequently Asked Questions
What type of mutation is sickle cell anemia?
Sickle cell anemia is a genetic mutation in the HBB gene that causes the formation of an abnormal hemoglobin, hemoglobin S, to form. These abnormal cells cause red blood cells to “sickle” or form in a rigid, C-shape.
Where is the mutation for sickle cell anemia found?
This mutation is most likely to be found in those of African descent. However, those of Hispanic or Mediterranean descent may have the sickle cell mutation as well.
Is sickle cell anemia a silent mutation?
Sickle cell anemia is not a silent mutation. A silent mutation doesn't change the sequence of building blocks (amino acids) in the protein the gene codes for. Instead, the sickle cell mutation is considered a point mutation. It results in a different amino acid being used in the protein it codes for.
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