Sickle Cell Disease (SCD)


Sickle cell disease (SCD) is an autosomal recessive disease and the most common genetic disease in the United States, predominantly affecting African Americans at a rate of approximately 1 in 500. One in 12 African Americans carry the recessive gene mutation, and around 300,000 infants are born with the disease each year.3  

The first case of SCD was officially described by Herrick in 1910 after noticing sickle-shaped red blood cells in a patient with anemia. While this was the earliest documented case of SCD, the disease has existed for at least 5000 years, mainly in Africa.1 It was discovered in 1949 that sickling of erythrocytes was a result of abnormal hemoglobin (HbS), and the point mutation responsible for HbS was discovered shortly after in 1957. Sickle cell anemia was the first human disease to be explained by a single nucleotide mutation.2 

Normal adult hemoglobin (HbA) is a soluble tetramer consisting of 2 alpha chains and 2 beta chains – it is the beta chain that is affected in SCD. Sickle cell disease is an overarching term that comprises a set of disorders characterized by at least 1 HbS allele and includes sickle cell anemia, sickle-hemoglobin C disease (HbS/C), sickle β-thalassemia, and other abnormal hemoglobin variants due to defects in the beta chain of hemoglobin (HbS/D, HbS/E, and HbS/O).4 The most common mutation is a substitution of valine for glutamic acid at position 6 on chromosome 11 (HbS), accounting for 60% to 70% of SCD cases in the United States.5,6 This alteration, while seemingly minor, renders the hemoglobin chain more hydrophobic, resulting in precipitation of the molecule and subsequent sickling. In heterozygous patients (HbS/A), 1 of the 2 beta chains are affected and, thus, most patients are asymptomatic. Homozygous patients (HbS/S) inherit 2 abnormal HbS genes and are symptomatic. Coexisting mutations appear to play a role in disease severity.6 Other less common genotypes associated with SCD are summarized in Table 1. 

The repercussion of abnormal amino acid composition of the beta globin molecule is an abnormal polymerization of hemoglobin that deforms erythrocytes. The sickle-shaped erythrocytes occlude small blood vessels, producing local hypoxia and vaso-occlusive crises. Additionally, the abnormal hemoglobin decreases the mean life span of erythrocytes from 120 days to around 15 days, resulting in anemia.7 

Symptoms of SCD are present early in life, sometimes as early as 6 months of age. Complications of SCD are due to vaso-occlusion and include, among others, vaso-occlusive crisis (characterized by severe pain), acute chest syndrome, vulnerability to encapsulated organisms (due to autosplenectomy), cerebrovascular events, splenic sequestration, priapism, and aplastic crisis.3 

The diagnosis of SCD is obtained using hemoglobin electrophoresis. Newborn screening is the most common protocol used for diagnosing SCD in the United States.6 Treatment is categorized into health maintenance, management of complications, and curative treatment. Health maintenance involves patient education, medications to improve anemia, vaccination, and infection prophylaxis with penicillin. Complications such as acute chest syndrome and vaso-occlusive crisis are generally managed with analgesics, hydration, and supportive care; however, this will vary depending on the complication. The only cure for SCD is a hematopoietic stem cell transplant (HSCT).6 Patients with SCD who do not receive HSCT have a reduced life expectancy and live 20 to 30 years less than the average person.3 Quality of life is also greatly reduced due to frequent hospital visits and painful vaso-occlusive episodes. 

Patients with SCD who are African American are often undertreated for pain and are more frequently written off as drug seekers compared to white Americans.8 Sickle cell disease, while one of the most common diseases in the world, was considered a neglected condition across the globe. Only recently has significant progress been made toward achieving a cure. The extent to which the racial disparity of SCD contributed to the lack of scientific progress is debatable; however, scholars argue that race and lack of economic incentives have had an undeniable impact.9 Thankfully, the field of SCD research has recently undergone a rejuvenation, and promising therapies are being developed. 

Table 1. Included disorders for sickle cell disease

DisorderAllelesDescription
Homozygous HbSHbS/SSubstitution of valine for glutamic acid (HbS) on both beta chains.6,9 
Sickle-hemoglobin C diseaseHbS/CSubstitution of valine for glutamic acid (HbS) on 1 beta chain, substitution of lysine for glutamate on the sixth position (HbC) of the second beta chain.6,10 
Sickle β-thalassemia HbS/β+ and HbS/β°HbS/β+: HbS + β-thalassemia minor (non-HbS beta chain mutation results in decreased production).Hb S/β°: HbS + β-thalassemia major (non-HbS beta chain mutation results in absent production).6,11
Sickle-hemoglobin D, O, and E diseaseHbS/D, HbS/O, HbS/EHbD: Substitution of glutamine for glutamic acid. HbO: Glutamic acid replaced by lysine at position 121 of the beta chain.HbE: Substitution of lysine for glutamic acid at position 26 of the beta chain.12  

 References

1. Winter WP. A brief history of sickle cell disease. Howard University Hospital. Accessed November 5, 2021.

2. Milestones in sickle cell disease. American Society of Hematology. December 5, 2008. Accessed November 5, 2021. 

3. Sedrak A, Kondamudi NP. Sickle cell disease. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021. Updated September 6, 2021. Accessed November 5, 2021. 

4. What is sickle cell disease? Centers for Disease Control and Prevention. Accessed November 5, 2021.

5. About sickle cell disease. National Human Genome Research Institute. Updated May 26, 2020. Accessed November 5, 2021.

6. Bender MA. Sickle cell disease. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993. Accessed November 5, 2021.

7. Milner PF, Charache S. Life span of carbamylated red cells in sickle cell anemia. J Clin Invest. 1973;52(12):3161-3171. doi:10.1172/JCI107516

8. Hoffman KM, Trawalter S, Axt JR, Oliver MN. Racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites. Proc Natl Acad Sci U S A. 2016;113(16):4296-4301. doi:10.1073/pnas.1516047113

9. Carroll AE. Sickle cell disease still tends to be overlooked. The New York Times. August 5, 2019. Accessed November 5, 2021.

10. 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 5, 2021.

11. Needs T, Gonzalez-Mosquera LF, Lynch DT. Beta thalassemia. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021. Updated July 18, 2021. Accessed November 5, 2021. 

 12. Hemoglobin D. ScienceDirect. Accessed November 5, 2021. 

Reviewed by Harshi Dhingra, MD, on 11/8/2021.

Reviewed by Harshi Dhingra, MD, on 11/8/2021.

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