Sickle cell disease (NORD)

Video summary

Sickle cell disease is an autosomal recessive genetic disorder, in which the beta-globin subunit of hemoglobin is misshapen, causing red blood cells to sickle when deoxygenated, which leads to their premature destruction as well as vaso-occlusion. Sickle-cell disease is associated with several acute and chronic health problems, such as severe infections, attacks of severe pain ("sickle-cell crisis"), stroke, and an increased risk of death.

Symptoms of sickle cell disease can vary and may include episodes of severe pain, fatigue, shortness of breath, anemia, and frequent infections. The severity and frequency of symptoms can vary widely among individuals with the condition, and some people may experience only mild symptoms, while others may have more severe and frequent episodes of pain and organ damage.

Treatment for sickle cell disease may involve pain management, blood transfusions, and antibiotics to prevent infections. In some cases, a bone marrow transplant may be necessary to cure the condition. Additionally, individuals with sickle cell disease may need to make lifestyle changes, such as avoiding extreme temperatures, staying hydrated, and managing stress, to help prevent and manage symptoms.

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Content Reviewers

Antonia Syrnioti, MD,Yifan Xiao, MD,Stacy Kruse, MD, FACP, Anna Hernández, MD,Filip Vasiljević, MD

In sickle cell disease, also known as sickle cell anemia, the term "sickle cell" refers to the crescent-shaped red blood cells due to abnormal hemoglobin structure. Moreover, sickle cell disease is caused by mutations in the HBB gene and represents the most common inherited hemoglobinopathy.

Healthy red blood cells, or erythrocytes, have a biconcave shape, looking like flattened discs. If we slice one open, you will notice it is not completely packed, meaning there’s more cell membrane than content inside. Inside, there’s hemoglobin, which is the protein responsible for carrying oxygen from the lungs to the rest of the body.

Imagine hemoglobin as marbles, and the red blood cell membrane as a plastic bag. If you fill the bag tightly with marbles, it won’t bend or fit through narrow pipes. But if you use a much larger bag for the same number of marbles, you could easily squeeze it through. That's exactly how red blood cells work. Their structure gives them flexibility to stretch and change shape as they squeeze through tiny capillaries without breaking.

Now, let's talk about hemoglobin itself. Hemoglobin is a tetramer, meaning it’s made up of 4 protein subunits, arranged in two pairs. Up until 6 months of age, most of our hemoglobin is fetal hemoglobin, or hemoglobin F, which consists of two alpha-globin chains and two gamma-globin chains. Around 6 months of age, the body shifts from hemoglobin F to the dominant adult form called hemoglobin A, which consists of two alpha-globin and two beta-globin chains. There’s also a small amount of hemoglobin A2, which contains two alpha-globin and two delta-globin chains.

Now, in sickle cell disease, there’s a mutation in the HBB gene that encodes beta-globin chains of hemoglobin. If a person inherits only one mutated copy of the gene, they are a carrier and do not develop the condition. These individuals have a sickle cell trait. However, if they inherit two mutated copies, they develop sickle cell disease. In other words, sickle cell disease is an autosomal recessive condition.

This mutation in the HBB gene affects the sixth amino acid of the beta-globin chain. Normally, glutamic acid is in this position, which is hydrophilic and loves water. However, in sickle cell disease, glutamic acid is replaced by valine, which is sticky and hydrophobic, meaning it repels water. So, instead of hemoglobin A, red blood cells are rich in hemoglobin S. While hemoglobin S can still carry oxygen, problems arise when it releases oxygen.