Thompson & Thompson Genetics in Medicine, 8th Edition

Case 42. Sickle Cell Disease (β-Globin Glu6Val Mutation, MIM 603903)

Autosomal Recessive

Principles

• Heterozygote advantage

• Novel property mutation

• Genetic compound

• Ethnic variation in allele frequencies

Major Phenotypic Features

• Age at onset: Childhood

• Anemia

• Infarction

• Asplenia

History and Physical Findings

For the second time in 6 months, a Caribbean couple brought their 24-month-old daughter, C.W., to the emergency department because she refused to bear weight on her feet. There was no history of fever, infection, or trauma, and her medical history was otherwise unremarkable; findings from the previous visit were normal except for a low hemoglobin level and a mildly enlarged spleen. Findings from the physical examination were normal except for a palpable spleen tip and swollen feet. Her feet were tender to palpation, and she would not stand up. Both parents had siblings who died in childhood of infection and others who may have had sickle cell disease. In view of this history and the recurrent painful swelling of her feet, her physician tested C.W. for sickle cell disease by hemoglobin electrophoresis. This test result documented sickle cell hemoglobin, Hb S, in C.W.

Background

Disease Etiology and Incidence

Sickle cell disease (MIM 603903) is an autosomal recessive disorder of hemoglobin in which the β subunit genes have a missense mutation that substitutes valine for glutamic acid at amino acid 6. The disease is most commonly due to homozygosity for the sickle cell mutation, although compound heterozygosity for the sickle allele and a hemoglobin C or a β-thalassemia allele can also cause sickle cell disease (see Chapter 11). The prevalence of sickle cell disease varies widely among populations in proportion to past and present exposure to malaria (see Table). The sickle cell mutation appears to confer some resistance to malaria and thus a survival advantage to individuals heterozygous for the mutation.

Pathogenesis

Hemoglobin is composed of four subunits, two α subunits encoded by HBA on chromosome 16 and two β subunits encoded by the HBB gene on chromosome 11 (see Chapter 11). The Glu6Val mutation in β-globin decreases the solubility of deoxygenated hemoglobin and causes it to form a gelatinous network of stiff fibrous polymers that distort the red blood cell, giving it a sickle shape (see Fig. 11-5). These sickled erythrocytes occlude capillaries and cause infarctions. Initially, oxygenation causes the hemoglobin polymer to dissolve and the erythrocyte to regain its normal shape; repeated sickling and unsickling, however, produce irreversibly sickled cells that are removed from the circulation by the spleen. The rate of removal of erythrocytes from the circulation exceeds the production capacity of the marrow and causes a hemolytic anemia.

Frequencies of the Sickle Cell Mutation among California Newborns

Ethnicity

Hb SS (Homozygote)

Hb AS (Heterozygote)

African American

1/700

1/14

Asian Indian

0/1600

1/700

Hispanic

1/46,000

1/180

Middle Eastern

0/22,000

1/360

Native American

1/17,000

1/180

Northern European

1/160,000

1/600

Asian

0/200,000

1/1300

As discussed in Chapter 11, allelic heterogeneity is common in most mendelian disorders, particularly when the mutant alleles cause loss of function. Sickle cell disease is an important exception to the rule because one specific mutation is responsible for the unique novel properties of Hb S. Hb C is also less soluble than Hb A, and also tends to crystallize in red cells, decreasing their deformability in capillaries and causing mild hemolysis, but Hb C does not form the rod-shaped polymers of Hb S.

Phenotype and Natural History

Patients with sickle cell disease generally present in the first 2 years of life with anemia, failure to thrive, splenomegaly, repeated infections, and dactylitis (the painful swelling of the hands or feet from the occlusion of the capillaries in small bones seen in patient C.W.; Fig. C-42). Vaso-occlusive infarctions occur in many tissues, causing strokes, acute chest syndrome, renal papillary necrosis, autosplenectomy, leg ulcers, priapism, bone aseptic necrosis, and visual loss. Bone vaso-occlusion causes painful “crises,” and, if untreated, these painful episodes can persist for days or weeks. The functional asplenia, from infarction and other poorly understood factors, increases susceptibility to bacterial infections such as pneumococcal sepsis and Salmonella osteomyelitis. Infection is a major cause of death at all ages, although progressive renal failure and pulmonary failure are also common causes of death in the fourth and fifth decades. Patients also have a high risk for development of life-threatening aplastic anemia after parvovirus infection because parvovirus infection causes a temporary cessation of erythrocyte production.

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FIGURE C-42 Acute dactylitis in a child with sickle cell disease. Radiographs of a child's hand during (left) and 2 weeks following (right) an attack of dactylitis. Note the development of destructive bony lesions. See Sources & Acknowledgments.

Heterozygotes for the mutation (who are said to have sickle cell trait) do not have anemia and are usually clinically normal. Under conditions of severe hypoxia, however, such as ascent to high altitudes, erythrocytes of patients with sickle cell trait may sickle and cause symptoms similar to those observed with sickle cell disease. With extreme exertion and dehydration, there is increased risk for rhabdomyolysis in sickle cell heterozygotes.

Management

In a given patient with sickle cell disease, there are no accurate predictors for the severity of the disease course. Although the molecular basis of the disease has been known longer than that of any other single-gene defect, current treatment is only supportive. No specific therapy that prevents or reverses the sickling process in vivo has been identified. Persistence of fetal hemoglobin greatly ameliorates disease severity. Several pharmacological interventions aimed at increasing fetal hemoglobin concentrations are under investigation (see Chapter 13), and hydroxyurea has been approved for this indication. Although gene therapy has the potential to ameliorate and cure this disease, effective β-globin gene transfer has been achieved in only a single patient (see Chapter 13). Allogeneic bone marrow transplantation is the only treatment currently available that can cure sickle cell disease.

Because of the 11% mortality from sepsis in the first 6 months of life, most states in the United States offer newborn screening for sickle cell disease to initiate antibiotic prophylaxis that is maintained through 5 years of age (see Chapter 18).

Inheritance Risk

Because sickle cell disease is an autosomal recessive disorder, future siblings of an affected child have a 25% risk for sickle cell disease and a 50% risk for sickle cell trait. With use of fetal DNA derived from chorionic villi or amniocytes, prenatal diagnosis is available by molecular analysis for the sickle cell mutation.

Questions for Small Group Discussion

1. What are the difficulties with gene therapy for this disorder?

2. Name two other diseases that may have become prevalent because of a heterozygote survival advantage. What is the rationale for hypothesizing a heterozygote advantage for those diseases?

3. Although it is always a severe disease, the severity of sickle cell disease is determined partially by the haplotype on which the mutation occurs. How could the haplotype affect disease severity?

4. Using the incidence figures in the Table, what is the risk that an unrelated African American woman and man of Northern European descent will have a child affected with sickle cell disease? with sickle cell trait?

References

Bender MA, Hobbs W. Sickle cell disease. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1377/.

Kanter J, Kruse-Jarres R. Management of sickle cell disease from childhood through adulthood. Blood Rev. 2013;27:279–287.

McGann PT, Nero AC, Ware RE. Current management of sickle cell anemia. Cold Spring Harb Perspect Med. 2013;3:a011817.

Serjeant GR. The natural history of sickle cell disease. Cold Spring Harb Perspect Med. 2013;3:a011783.