Sickle Cell Disease (SCD)


Sickle cell disease (SCD) is caused by mutations in the HBB gene,1 which encodes for the beta chain of the adult hemoglobin protein (HbA). The mutated gene produces a defective beta-globin chain called hemoglobin S (HbS) that polymerizes and causes the deformation of red blood cells (RBCs) into a sickle shape, resulting in decreased RBC lifespan and hemolysis. These inflexible sickle-shaped RBCs can also block the normal flow of blood in blood vessels (vaso-occlusion), depriving the tissues or organs of oxygen and leading to damage.1

Inheritance

Sickle cell disease is inherited in an autosomal recessive pattern, which means that a child is born with SCD only when they inherit 2 defective copies of the sickle cell gene (1 from each parent). If a child has only 1 copy of the defective gene and the other gene is normal, they will be a carrier who may transmit the defective gene to their children but will not have the disease themselves. In some cases, carriers may manifest mild symptoms.

If both parents are carriers, there is a 25% risk of having a child with SCD, a 50% risk of having a child who is a carrier, and a 25% chance of having a normal child without an HBB gene mutation.2

Genetic Forms of Sickle Cell Disease

Some patients with SCD get the sickle cell mutation from one parent and a different mutation from the other. Thus, SCD exists in different forms depending on the inherited genetic mutations in the HBB gene, including sickle beta-thalassemia and sickle cell-hemoglobin C disease. It is important to diagnose which form of SCD affects an individual to be able to treat the condition effectively.3

Homozygous Sickle Cell Disease

Homozygous SCD, also called sickle cell anemia or HbSS disease, is the the most common and severe form of SCD in which HbS is inherited from both parents and replaces both of the beta-globin subunits in hemoglobin. It is caused by a single nucleotide mutation (GAG codon changing to GTG) in the HBB gene that results in hydrophilic glutamate being substituted with hydrophobic valine at position 6 of the beta-globin chain, producing defective HbS instead of normal HbA. Under low oxygen conditions, this valine forms hydrophobic interactions with other hydrophobic residues on other HbS molecules, leading to HbS polymerization and the characteristic sickled RBC shape.4 The prevalence of this disease decreases with age, reflecting a higher mortality rate at an early age. The symptom severity varies from mild, with patients surviving beyond the age of 50 years, to severe, with complications resulting in early death.

Sickle Cell-Hemoglobin C Disease

Sickle cell-hemoglobin C disease, also called HbSC disease, is caused by the inheritance of the HbS gene mutation from one parent and the HbC gene mutation from the other. HbC mutation causes the substitution of glutamate with lysine at the sixth position of the beta-globin chain. The disease is generally mild, and survival is similar to that of the general population. Patients may suffer from proliferative retinopathy due to a lack of adequate oxygen supply to the eyes.5,6

Sickle Cell-Beta0 Thalassemia

Sickle cell-β0 thalassemia is caused by the inheritance of the β0 thalassemia gene (with no production of normal hemoglobin) from one parent and the HbS gene from the other, resulting in a condition similar to HbSS disease. The “zero” denotes the absence of normal hemoglobin, and thus sickle cell-beta0 thalassemia is a severe condition.7

Sickle Cell-Beta+ Thalassemia

Sickle cell-β+ thalassemia is caused by the inheritance of the β+ thalassemia gene (with some production of normal hemoglobin) from one parent and the HbS gene from the other. The “plus” signifies that there is some production of normal hemoglobin, but it is lower than that seen in healthy individuals. Patients with sickle cell-β+ thalassemia are less severely affected than those with sickle cell-beta0 thalassemia.7

References

  1. HBB gene. MedlinePlus. Updated August 18, 2020. Accessed November 29, 2021.
  2. Sickle cell disease. National Organization for Rare Disorders (NORD). Accessed November 29, 2021.
  3. Serjeant GR. The geography of sickle cell disease: opportunities for understanding its diversity. Ann Saudi Med. 1994;14(3):237-246. doi:10.5144/0256-4947.1994.237
  4. Odièvre MH, Verger E, Silva-Pinto AC, Elion J. Pathophysiological insights in sickle cell disease. Indian J Med Res. 2011;134(4):532-537.
  5. Hemoglobin SC disease. Genetic and Rare Diseases Information Center (GARD). Updated November 11, 2016. Accessed November 29, 2021. 
  6. Karna B, Jha SK, Al Zaabi E. Hemoglobin C disease. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021. Updated July 6, 2021. Accessed November 29, 2021.
  7. Sickle beta thalassemia. Genetic and Rare Diseases Information Center (GARD). Updated December 22, 2014. Accessed November 29, 2021.

Reviewed by Debjyoti Talukdar, MD, on 11/26/2021.

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