Sickle Cell Disease (SCD)


Sickle cell disease (SCD) is a common hereditary hemoglobinopathy resulting from a point mutation in the gene that codes for the beta subunit of hemoglobin, located on chromosome 11. When deoxygenated, the abnormal hemoglobin S (HbS) molecules polymerize, causing the red cells to assume a sickle shape. Episodes of hemolytic anemia, microvascular blockage, and ischemic tissue damage are features of this disease.1 SCD is an increasing health issue globally.2

The inheritance of SCD is autosomal recessive. It is the most common genetic disorder in the United States, affecting predominantly African Americans, among whom the prevalence is approximately 1 in 500. Approximately 1 in 12 African Americans carry the mutation, and approximately 300,000 infants are born with sickle cell anemia (SCA) each year.3 Chronic hemolytic anemia, sudden episodes of pain, and extensive organ damage characterize SCA, the most common form of SCD. In 2010, the number of children born with SCA in sub-Saharan Africa was reported to be 230,000, accounting for 75% of all SCA births globally. Sickle cell-hemoglobin C (HbSC) disease, the second most common type of SCD, occurs most frequently in West Africa. The clinical severity of SCA is highly variable, as is the life expectancy of affected individuals.4

Genetic Defects

SCD is a multiorgan disease in which a genetic mutation2 causes valine to be substituted for glutamic acid at position 6 of the beta chain of hemoglobin.3 As a result of the substitution, deoxygenated hemoglobin molecules polymerize, changing the shape of red blood cells and reducing their capacity for deformation. Increased adherence of red blood cells causes heterocellular aggregates to form, resulting in small-vessel blockage and local hypoxia. This process sets in motion a vicious cycle of increased HbS synthesis, release of inflammatory mediators, free radical formation, and reperfusion injury.3 Types of SCD are the following:

Sickle cell disease (HbSS; homozygous for hemoglobin S)

SCA, also known as HbSS disease, is the most common and severe form of SCD. Affected individuals are homozygous for the mutant allele.5 In this type of SCD, 2 sickle cell alleles (S) are inherited, 1 from each parent.6

Sickle-hemoglobin C disease (HbSC)

Individuals with this type of SCD inherit an S allele from 1 parent and another abnormal hemoglobin allele (C) from the other parent. This type of SCD is frequently relatively mild.6

Sickle-β-thalassemia disease (HbS/β+-thalassemia and HbS/β°-thalassemia)

Individuals with sickle cell-β-thalassemia disease inherit an S allele from 1 parent and a β-thalassemia allele from the other parent. β-Thalassemia is divided into 2 types: zero and plus. Patients with HbS/β°-thalassemia typically have a severe form of SCD,6 caused by the simultaneous inheritance of β°-thalassemia and a sickle cell mutation. Phenotypically, it resembles HbSS disease.5 Patients with HbS/β+-thalassemia have a milder type of SCD.6 

Sickle-hemoglobin D, E, and O disease (HbSD, HbSE, and HbSO)

These types of SCD are caused by the inheritance of 1 S allele and 1 allele for another abnormal hemoglobin (D, E or O). These uncommon kinds of SCD vary in severity.6 

Sickle cell trait (HbAS)

Sickle cell trait (SCT) is caused by heterozygosity. Persons with HbAS, or SCT, are not considered to be part of the SCD spectrum because they rarely exhibit classic SCA symptoms. SCT may be identified only by screening, as is done during childbirth, blood donation, and other, similar situations.5 Patients with SCT acquire a normal allele (A) from 1 parent and an S allele from the other. Patients with SCT normally have no symptoms and lead normal lives, although they can transmit the condition to their children.6

Mutation and Its Characteristics

The beta chain of hemoglobin is a single chain comprising 147 amino acids.The beta globin gene is mutated in SCA. The resultant abnormal protein also has 147 amino acids; however, the amino acid at position 6 in the chain is valine instead of glutamic acid owing to the single-base mutation.7

HbS molecules bind together to create rigid rods. The condition is named for the malformed, sickle-like shape that the rods cause erythrocytes to assume. The sickle-shaped erythrocytes do not transport oxygen properly and tend to block capillaries, closing off the blood supply to many organs, including the brain and heart resulting in excruciating pain due to vaso-occlusion. All this results from a single nucleotide mutation. SCA is a unique life-threatening disease linked to a single variation in 1 among 3 billion adenosine, thymine, cytosine, and guanine nucleotides in the human genome.7

Inheritance Pattern

SCA is an autosomal recessive disease, in which affected individuals carry 2 mutant alleles. Each parent of a person with an autosomal recessive disorder generally carries 1 mutant allele, but they usually do not have any clinical features of the disease. A person who carries 1 SCA mutant allele is a carrier of the disease, or has SCT. When 2 carriers of an autosomal recessive condition like SCD have children, there is a 25% (1 in 4) probability that each child will carry 2 alleles and have the condition; a 50% (1 in 2) probability that each child will carry 1 allele, like the 2 parents; and a 25% (1 in 4) probability that each child will carry no mutant alleles and so will not be a carrier and will not have the condition.8

References

  1. Kumar V, Abbas AK, Aster JC. Red blood cell and bleeding disorders. In: Robbins & Cotran Pathologic Basis of Disease, 10th ed. Amsterdam, The Netherlands: Elsevier; 2020:641.
  2. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376(16):1561-1573. doi:10.1056/NEJMra1510865
  3. Sedrak A, Kondamudi NP. Sickle cell disease. StatPearls. Updated September 6, 2021. Accessed November 8, 2021. 
  4. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010. doi:10.1038/nrdp.2018.10
  5. Mangla A, Ehsan M, Agarwal N, Maruvada S. Sickle cell anemia. StatPearls. October 10, 2021. Accessed November 8, 2021.
  6. What is sickle cell disease? Centers for Disease Control and Prevention. Reviewed December 14, 2020. Accessed November 8, 2021.
  7. Clancy S. Genetic mutation. Nature Education. 2008;;1(1):187.
  8. Sickle cell anemia. Genetic and Rare Diseases Information Center (GARD). Accessed November 8, 2021.

Reviewed by Kyle Habet, MD, on 11/15/2021.

Reviewed by Kyle Habet, MD, on 11/15/2021.

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