Sickle Cell anemia
Sickle-cell anemia (SS) is a group of genetic
disorders caused by sickle hemoglobin (Hgb S or Hb S).
In many forms of the disease, the red blood cells change
shape upon deoxygenation because of polymerization of
the abnormal sickle hemoglobin; the hemoglobin proteins
stick to each other, causing the cell to get a rigid
surface and sickle shape. This process damages the red
blood cell membrane, and can cause the cells to become
stuck in blood vessels. This deprives the downstream
tissues of oxygen and causes ischemia and infarction,
which may cause organ damage, such as stroke. The disease
is chronic and lifelong. Individuals are most often
well, but their lives are punctuated by periodic painful
attacks. Life-expectancy is shortened, but contemporary
survival data is lacking. Older studies indicated that
sufferers could live to an average of 40 to 50 years,
with the average age for males being 42 and the average
age for females being 48. Sickle-cell disease occurs
more commonly in people (or their descendants) from
parts of the world such as sub-Saharan Africa, where
malaria is or was common, but it also occurs in people
of other ethnicities. This is because those with one
or two alleles of the sickle cell disease are resistant
to malaria since the red blood cells are not conducive
to the parasites - in areas where malaria is common
there is a survival value in carrying the sickle cell
genes. The mutated allele has incomplete dominance,
which means that an individual who carries the sickle
cell genes but does not have the disease still retains
immunity to malaria.
Genetic Prevalence
Sickle-cell anaemia is caused by a point mutation in
the ß-globin chain of haemoglobin, replacing the
amino acid glutamic acid with the less polar amino acid
valine at the sixth position of the ß chain. The
beta-globin gene is found on the short arm of Chr. 11.
The association of two wild-type a-globin subunits with
two mutant ß-globin subunits forms haemoglobin
S, which polymerises under low oxygen conditions causing
distortion of red blood cells and a tendency for them
to lose their elasticity.
New erythrocytes are quite elastic, which allows the
cells to deform to pass through capillaries. Often a
cycle occurs because as the cells sickle, they cause
a region of low oxygen concentration which causes more
red blood cells to sickle. Repeated episodes of sickling
causes loss of this elasticity and the cells fail to
return to normal shape when oxygen concentration increases.
These rigid red blood cells are unable to flow through
narrow capillaries, causing vessel occlusion and ischaemia.
In people heterozygous for HgbS (carriers of sickling
haemoglobin), the polymerisation problems are minor.
In people homozygous for HgbS, the presence of long
chain polymers of HbS distort the shape of the red blood
cell, from a smooth donut-like shape to ragged and full
of spikes, making it fragile and susceptible to breaking
within capillaries. Carriers only have symptoms if they
are deprived of oxygen (for example, while climbing
a mountain) or while severely dehydrated. Normally these
painful crises occur 0.8 times per year per patient.
The sickle cell disease occurs when the seventh amino
acid (if we count the initial methionine), glutamic
acid is replaced by valine to change is structure and
function.
The gene defect is a known mutation of a single nucleotide
(see single nucleotide polymorphism - SNP) (A to T)
of the ß-globin gene, which results in glutamate
to be substituted by valine at position 6. Haemoglobin
S with this mutation are referred to as HbS, as opposed
to the normal adult HbA. The genetic disorder is due
to the mutation of a single nucleotide, from a GAG to
GUG codon mutation. This is normally a benign mutation,
causing no apparent effects on the secondary, tertiary,
or quaternary structure of haemoglobin. What it does
allow for, under conditions of low oxygen concentration,
is the polymerization of the HbS itself. The deoxy form
of haemoglobin exposes a hydrophobic patch on the protein
between the E and F helices. The hydrophobic residues
of the valine at position 6 of the beta chain in haemoglobin
are able to bind to the hydrophobic patch, causing haemoglobin
S molecules to aggregate and form fibrous precipitates.
The allele responsible for sickle-cell anaemia is autosomal
recessive and can be found on the short arm of chromosome
11. A person who receives the defective gene from both
father and mother develops the disease; a person who
receives one defective and one healthy allele remains
healthy, but can pass on the disease and is known as
a carrier. If two parents who are carriers have a child,
there is a 1-in-4 chance of their child developing the
illness and a 1-in-2 chance of their child just being
a carrier. Since the gene is incompletely recessive,
carriers have a few sickle red blood cells at all times,
not enough to cause symptoms, but enough to give resistance
to malaria. Because of this, heterozygotes have a higher
fitness than either of the homozygotes. This is known
as heterozygote advantage.
Due to the evolutionary advantage of the heterozygote,
the illness is still prevalent, especially among people
with recent ancestry in malaria-stricken areas, such
as Africa, the Mediterranean, India and the Middle East.
Inheritance
• Sickle-cell conditions are inherited from parents
in much the same way as blood type, hair color and texture,
eye color and other physical traits.
• The types of haemoglobin a person makes in the
red blood cells depend upon what haemoglobin genes the
person inherits from his parents
Examples
1. If one parent has sickle-cell anaemia
("SS" in the diagram) and the other is Normal
(AA), all of their children will have sickle cell trait
(AS).
2. If one parent has sickle-cell anaemia
(SS) and the other has Sickle Cell Trait (AS), there
is a 50% chance (or 1 out of 2) of a child having sickle
cell disease (SS) and a 50% chance of a child having
sickle cell trait (AS).
3. When both parents have sickle cell
trait (AS), they have a 25% chance (1 of 4) of a child
having sickle cell disease (SS), as shown in the diagram.
Sickle-cell anemia appears to be caused by a recessive
allele. Two carrier parents have a one in four chance
of having a child with the disease. The child will be
homozygous recessive.
However, it has been argued that the allele, although
appearing outwardly recessive, is in fact co-dominant,
due to the resistance to a malaria which is obtained
by those of the AS genotype. Since a separate phenotype
from that of Normal (AA) has therefore been expressed,
it is impossible to argue that the S allele is homozygous
recessive.
Management
Various approaches are being sought for preventing sickling
episodes as well as for the complications of sickle-cell
disease. Gene therapy is under investigation. People
who are known carriers of the disease often undergo
genetic counseling before they have a child. A test
to see if an unborn child has the disease takes either
a blood sample from the unborn or a sample of amniotic
fluid. Since taking a blood sample from a fetus has
risks, the latter test is usually used. Screening for
the Sickle Cell Anemia is one of the major parts of
the Premarital Screening.
STEP 1
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