What causes sickle cell disease

Overview

Sickle cell disease (SCD) is a group of inherited red blood cell disorders. Normally, red blood cells are round and flexible, moving easily through blood vessels to deliver oxygen throughout the body. In people with SCD, however, red blood cells are abnormally shaped, often resembling a sickle or crescent moon. These sickle-shaped cells are rigid and sticky, and they tend to block blood flow, leading to a range of health problems.

The root cause of sickle cell disease lies in a genetic mutation that affects hemoglobin, the protein within red blood cells responsible for carrying oxygen. Hemoglobin is made up of two protein chains: alpha-globin and beta-globin. In SCD, there is a specific mutation in the gene that codes for the beta-globin chain, known as the HBB gene. This mutation causes the production of an abnormal type of hemoglobin, called hemoglobin S (HbS).

Understanding the Genetics

Sickle cell disease is an inherited condition, meaning it is passed down from parents to children through genes. It follows an autosomal recessive inheritance pattern. This means that for a person to have sickle cell disease, they must inherit two copies of the mutated HBB gene – one copy from each parent. If a person inherits only one copy of the mutated gene and one normal copy, they are said to be a carrier of the sickle cell trait. Carriers usually do not have symptoms of sickle cell disease but can pass the gene on to their children.

When two carriers of the sickle cell trait have a child, there is a 25% chance with each pregnancy that the child will inherit two copies of the mutated gene and thus have sickle cell disease. There is also a 50% chance the child will be a carrier, and a 25% chance the child will inherit two normal genes and not have SCD or the trait.

The Role of Hemoglobin

Hemoglobin is crucial for life, as it binds to oxygen in the lungs and transports it to all tissues and organs. There are several types of hemoglobin, with hemoglobin A (HbA) being the most common type in healthy individuals. In sickle cell disease, the mutation in the HBB gene leads to the production of abnormal hemoglobin S (HbS). When HbS molecules are in an environment with low oxygen, they can stick together and form long, rod-like structures. These structures distort the red blood cells into their characteristic sickle shape.

The consequences of this sickling are significant. Sickle-shaped red blood cells are more fragile and break apart easily, leading to a shortage of red blood cells, a condition known as anemia. They are also less flexible than normal red blood cells and can get stuck in narrow blood vessels, obstructing blood flow. This blockage, known as a vaso-occlusive crisis, can cause severe pain, organ damage, and other serious health complications.

Types of Sickle Cell Disease

There are several types of sickle cell disease, primarily determined by the specific combination of hemoglobin types inherited. The most common and often most severe form is sickle cell anemia, also known as hemoglobin SS disease (HbSS). This occurs when a person inherits the HbS gene from both parents.

Other types include:

• Sickle cell-hemoglobin C disease (HbSC): Inheriting the gene for HbS from one parent and the gene for hemoglobin C (HbC) from the other.
• Sickle cell-beta thalassemia (HbS/beta-thalassemia): This involves inheriting the HbS gene from one parent and a gene for beta-thalassemia from the other. Thalassemia is another blood disorder that affects hemoglobin production. There are two types:
• Beta-zero thalassemia: No beta-globin is produced.
• Beta-plus thalassemia: Some, but not enough, beta-globin is produced.
• Sickle cell-hemoglobin D (HbSD) disease: Less common, involves HbS and another abnormal hemoglobin.
• Sickle cell-hemoglobin E (HbSE) disease: Also less common, involves HbS and HbE.

While sickle cell trait (HbAS) is often discussed alongside SCD, it is important to distinguish it. Individuals with sickle cell trait have one normal hemoglobin gene and one sickle cell gene. They typically do not experience the symptoms of sickle cell disease, although in rare circumstances, they may experience health issues, particularly under extreme conditions like severe dehydration or low oxygen levels.

Prevalence and Risk Factors

Sickle cell disease is most common among people of African, Mediterranean, Middle Eastern, and Indian descent. In the United States, it disproportionately affects the Black or African American population. This is due to the historical prevalence of the sickle cell gene in populations that were historically exposed to malaria, as the sickle cell trait offers some protection against this parasitic disease.

Globally, SCD affects millions of people. It is estimated that over 300,000 babies are born with sickle cell disease each year worldwide. In the United States, about 1 in every 365 Black or African American births and 1 in every 16,300 Hispanic births are affected by sickle cell anemia. The carrier rate for sickle cell trait is higher, affecting about 1 in 13 Black or African American babies.