Genetics of Sickle Cell Anemia

Sickle cell anemia was the first genetic disease to be characterized at the molecular
level. The mutation responsible for sickle cell anemia is smalljust ONE nucleotide
of DNA out of the three billion in each human cell. Yet it is enough to change the
chemical properties of hemoglobin, the iron and protein complex that carries oxygen
within red blood cells.

There are approximately 280 million hemoglobin molecules in each red blood cell
(RBC). The protein portion of hemoglobin consists of four globin subunits: two alpha
() and two beta (). These two types of subunits are encoded by the and globin
genes, respectively. While the binding of oxygen actually occurs at the iron sites, all
four globin chains must work together in order for the process to function well.

Sickle cell anemia, also known as sickle cell disease, is caused by a point mutation in
the globin gene. As a result of this mutation, valine (a non-polar amino acid) is
inserted into the globin chain instead of glutamic acid (an electrically charged
amino acid). The mutation causes the RBCs to become stiff and sometimes sickle-
shaped when they release their load of oxygen. The sickle cell mutation produces a
sticky patch on the surface of the chains when they are not complexed with
oxygen. Because other molecules of sickle cell hemoglobin also develop the sticky
patch, they adhere to each other and polymerize into long fibers that distort the RBC
into a sickle shape.

The sickled cells tend to get stuck in narrow blood vessels, blocking the flow of
blood. As a result, those with the disease suffer painful crises in their joints and
bones. They may also suffer strokes, blindness, or damage to the lungs, kidneys, or
heart. They must often be hospitalized for blood transfusions and are at risk for a life-
threatening complication called acute chest syndrome. Although many sufferers of
sickle cell disease die before the age of 20, modern medical treatments can sometimes
prolong these individuals lives into their 40s and 50s.

There are two globin alleles important for the inheritance of sickle cell anemia: A
and S. Individuals with two normal A alleles (AA) have normal hemoglobin, and
therefore normal RBCs. Those with two mutant S alleles (SS) develop sickle cell
anemia. Those who are heterozygous for the sickle cell allele (AS) produce both
normal and abnormal hemoglobin. Heterozygous individuals are usually healthy, but
they may suffer some symptoms of sickle cell anemia under conditions of low blood
oxygen, such as high elevation. Heterozygous (AS) individuals are said to be
carriers of the sickle cell trait. Because both forms of hemoglobin are made in
heterozygotes, the A and S alleles are codominant.

Disease Description

Sickle cell anemia is an inherited blood disorder characterized primarily by chronic

anemia and periodic episodes of pain. The underlying problem involves hemoglobin,
a component of red blood cells. Hemoglobin molecules in each red blood cell carry
oxygen from the lungs to body organs and tissues and bring carbon dioxide back to
the lungs.

In sickle cell anemia, the hemoglobin is defective. After hemoglobin molecules give
up their oxygen, some may cluster together and form long, rod-like structures. These
structures cause red blood cells to become stiff and assume a sickle shape.

Unlike normal red cells, which are usually smooth and donut-shaped, sickled red cells
cannot squeeze through small blood vessels. Instead, they stack up and cause
blockages that deprive organs and tissues of oxygen-carrying blood. This process
produces periodic episodes of pain and ultimately can damage tissues and vital organs
and lead to other serious medical problems. Normal red blood cells live about 120
days in the bloodstream, but sickled red cells die after about 10 to 20 days. Because
they cannot be replaced fast enough, the blood is chronically short of red blood cells,
a condition called anemia.

Inheritance

Sickle cell anemia is an autosomal recessive genetic disorder caused by a defect in the
HBB gene, which codes for hemoglobin. The presence of two defective genes (SS) is
needed for sickle cell anemia. If each parent carries one sickle hemoglobin gene (S)
and one normal gene (A), each child has a 25% chance of inheriting two defective
genes and having sickle cell anemia; a 25% chance of inheriting two normal genes
and not having the disease; and a 50% chance of being an unaffected carrier like the
parents.

Incidence

Sickle cell anemia affects millions throughout the world. It is particularly common
among people whose ancestors come from sub-Saharan Africa; Spanish-speaking
regions (South America, Cuba, Central America); Saudi Arabia; India; and
Mediterranean countries such as Turkey, Greece, and Italy. In the Unites States, it
affects around 72,000 people, most of whose ancestors come from Africa. The disease
occurs in about 1 in every 500 African-American births and 1 in every 1000 to 1400
Hispanic-American births. About 2 million Americans, or 1 in 12 African Americans,
carry the sickle cell trait.

Etiology and Epidemiology

Sickle cell disease (SCD) is a potentially devastating condition that is caused by

an autosomal recessive inherited hemoglobinopathy, which results in the
hallmark clinical sequelae of vasoocclusive phenomena and hemolysis. The
genetic abnormality is due to a substitution of the amino acid valine for glutamic
acid at the sixth position on the beta globin chain and was first described over
one hundred years ago.

Hemoglobin S (HbS), the hemoglobin that is produced as a result of this defect, is

a hemoglobin tetramer (alpha2/beta S2) that is poorly soluble and polymerizes
when deoxygenated.

Overall, the incidence of sickle cell disease exceeds that of most other serious
genetic disorders, including cystic fibrosis and hemophilia.
It is seen worldwide but occurs most frequently in Africans and less commonly
in those of Mediterranean, Latino, East Indian, and Arab descent.
It is estimated that 16% of the population in Africa has a sickle
hemoglobinopathy which is the highest proportion worldwide. The Americas
and the East Mediterranean region represent the next highest proportion of
sickle cell hemoglobinopathy as delineated by the World Health Organization.

SCD results from any combination of the sickle cell gene with any other
abnormal -globin gene and there are many types of SCD. The most common
types include sickle cell anemia (Hb SS), the sickle beta-thalassemias (Hb S 0
and Hb S +), hemoglobin SC disease (Hb SC) and sickle cell disease with
hereditary persistence of fetal hemoglobin (S/HPFH). HbSS is the most common
form of sickle cell disease. Patients with Hb SS and Hb S0, in general, have the
most severe forms of SCD including lower hemoglobin levels and more frequent
vasoocclusive and hemolytic complications. Sickle-C (Hb SC) disease is the
second most common form of SCD. Patients with this type of SCD generally have
a more benign clinical course than do patients with Hb SS or sickle 0-
thalassemia. Likewise, patients with Sickle + -thalassemia and S/HPFH also
generally have a more benign clinical course and patients with S/HPFH may
actually have hemoglobin levels that are or approach normal.

Adults with sickle cell disease who live in the United States have a decreased life
expectancy with the odds of surviving beyond the 7th decade of life reported to
be less than 30%.

Historically, Platt et al. reported a large number of adults with sickle cell disease
who died during acute sickle cell related complications such as pain, acute chest
syndrome, and stroke.

In this era, the most common causes of death in adults from sickle cell disease
reported are pulmonary hypertension, sudden death of unknown etiology, renal
failure, and infection.

With regard to children with SCD, in the developed world, the mortality rate is
estimated to be as low as 0.5-1.0 per 100,000 children. This is in contrast to
higher rates in developing countries such as the Republic of Benin which
recently reported a mortality rate of 15.5 per 1,000 children (or 1,550 per
100,000 children).

The most common causes of death in childhood from sickle cell disease are
infection, acute chest syndrome and stroke.

Pathophysiology

There is a large amount of heterogeneity in the expression of sickle cell disease

which is not fully explained by the single mutation or different variants of
hemoglobin S. This variability is manifest by a wide spectrum in both frequency
and intensity of painful vaso-occlusive crises as well as highly variable degrees of
organ dysfunction. The pathophysiologic processes that lead to sickle cell disease
related complications result from a combination of hemolysis and vaso-
occlusion. Hemolysis occurs as a result of repeated episodes of hemoglobin
polymerization/depolymerization as sickle red blood cells pick up and release
oxygen in the circulation. Red blood cell membranes become abnormal from this
process and red blood cells have a shortened lifespan. Hemolysis can occur both
chronically and during 3 acute painful vaso-occlusive crises and also results in
the release of substantial quantities of free hemoglobin into the vasculature.
This resultant free ferrous hemoglobin likely consumes significant quantities of
nitric oxide (NO), which in turn, leads to abnormal regulation in vascular
homeostasis.

In addition to hemolysis, intermittent episodes of vascular occlusion cause tissue

ischemia, a major morbid component of the disorder which results in acute and
chronic multi-organ dysfunction, and which is characterized by chronic
inflammation and ischemia-reperfusion injury. Data suggest that neutrophils
play a key role in the tissue damage which occurs as both neutrophil numbers
are increased and evidence suggests that they are abnormally activated and
adherent.

Likewise, recent data suggest that sickle red cells induce adhesion of
lymphocytes and monocytes to the endothelium such that these may contribute
to the pathogenesis of vascular occlusion.

Figure 1.
Hemolysis contributes to the pathophysiology of sickle cell disease by reducing nitric oxide
bioavailability.
Modified from Ataga KI, Stocker J. Senicapoc (ICA-17043): a potential therapy for the prevention and
treatment of hemolysis-associated complications in sickle cell anemia. Expert Opin Investig. Drugs
2009;18:231239.
ADMA indicates asymmetric dimethylarginine; Hb, hemoglobin; HbS, sickle hemoglobin; RBC, red
blood cell.