The topic of focus in this essay is


The topic of focus in this essay is sickle cell
disease, which is a genetically inherited disorder that affects the blood. In
this essay the aim is to provide a
description of sickle cell disease in relation to how it is inherited and how
it affects a person’s health. The essay will follow an order as follows; firstly,
the pattern of inheritance will be defined, then the biology of the disease
will be explored and lastly the techniques
by which the disease is diagnosed will be described.

Pattern
of Inheritance

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Sickle cell disease occurs because of a mutation in
the beta-globin gene (1). It is an
autosomal recessive disease, which means that two copies of the mutated gene,
one from each parent, are required for the disease to manifest. If a mother and
father are both heterozygous carriers of the mutated gene their children have a
25% chance of being affected by the disease and 50% of their children are
likely to be carriers. Autosomal recessive diseases characteristically tend to
skip generations and males and females are equally affected (2)(3).

Interestingly, although sickle cell disease is life
threatening and affects children, it is very common in some parts of the world
seemingly due to its correlation with malaria. People who have sickle cell
trait, that is those who are heterozygous for the sickle cell allele, seem to
have a level of protection against malaria, meaning sickle cell carriers have
an evolutionary selective advantage in countries where malaria occurrence is
high, for example Africa. This  unfortunately
has the result that the mutated gene is carried on through the generations.(4)(5)

Biology of the Disease

Cause

The cause of sickle cell disease is defective
haemoglobin. For context, haemoglobin is the molecule needed to carry oxygen in
red blood cells. It is a protein comprised of four peptide chains which are
bound to a haem group. Although there are many combinations of these chains, it
is predominantly Haemoglobin A (HbA) which is found in adult blood and consists
of two alpha-globin chains and two beta-globin chains (6). In people with
sickle cell disease there was found to be a single nucleotide non-conservative
missense mutation in the beta-globin gene. This mutation causes the sixth amino
acid of beta-globin which is normally the hydrophilic glutamic acid to be
replaced with hydrophobic valine.(1) A haemoglobin
molecule with two alpha-globin chains and two mutated beta-globin chains is
referred to as sickle haemoglobin (HbS). It is interesting to note that sickle
cell disease was the first monogenic disease identified and it became a model
for subsequent diseases which could be traced to a point mutation in a specific
gene. (7)(8)

Effect

As a consequence of valine being hydrophobic, HbS
changes shape when deoxygenated. It is this change in shape which allows many
HbS molecules to bond together and form polymers, which causes red blood cells
to be altered into a crescent or sickle shape (9). The factors that
encourage red blood cells to sickle are hypoxia, acidosis and dehydration which
can all be improved with the oxygen and fluids as fundamental treatments. Sickle
cell carriers, despite not having the disease, can experience symptoms when
subject to extreme dehydration or high altitudes. The sickling of red bloods
cells in homozygous individuals causes serious health problems due to two main
factors; weakening of the cell membrane and vaso-occlusion (6)(10).

Anaemia is the direct result of the weakened cell
membrane as intravascular haemolysis which is premature destruction of sickled
red blood cells occurs. As red blood cells disintegrate, free haemoglobin is
released into the blood plasma and is bound by haptoglobin, so low haptoglobin
levels are an indicator of haemolysis. In addition, haem groups are recycled
and result in the production of unconjugated bilirubin, an excess of which
causes conditions such as sclera icterus, jaundice and gallstones (11). In response to
anaemia, the bone marrow produces an increased amount of reticulocytes
(immature RBCs) which leads to new bone formation leading to expansion of
medullary cavities in skull leading to enlarged cheeks. Anaemia can also cause
extramedullary hematopoiesis (RBC production outside the bone marrow) often in
the liver causing hepatomegaly (enlarged liver).

Vaso-occlusion tends to occur in the capillaries due
to the shape of sickled red blood cells and can have devastating effects. Dactylitis
is observed in children with sickle cell disease, which is painful swelling of
the digits due to clogging of blood flow in hands and feet. As the patients
life progresses other bones are affected causing sickle cell pain crises and
avascular necrosis (12). Red blood cells
can also clog up the spleen which can lead to an infarct to the spleen as well
as an enormous backup of blood in the spleen (splenic sequestration) which can
be life threatening. Over time splenic infarcts can scar the spleen so much
that it results in an auto-splenectomy. Without a functional spleen a person is
vulnerable to bacterial infections such as pneumonia, influenza, meningitis and
salmonella (6). Sickle red blood
cells can also form blockages in the cerebral vasculature causing brain
diseases such as stroke (13). Sickle red blood
cells can get stuck in the blood vessels of the lungs leading to acute chest
syndrome (14). In the kidneys,
clogging can cause necrosis which causes blood and proteins to enter the urine (15). Another problem
that men experience is priapism, a painful prolonged erection due to blockage
of capillaries in the penis (16).

Diagnosis

Sickle cell disease can be diagnosed by many means
including looking for sickle cells in blood smears, identifying HbS using
protein electrophoresis or restriction site analysis (1)(10). It is important
to diagnose this disease as early as possible as early treatment can prevent
many complications and in some countries, it is included in the new-born blood
spot screen test (17).

Conclusion

In summary, sickle cell disease is a hereditary
condition with an autosomal recessive pattern of inheritance. It is caused by a
mutation in the beta-haemoglobin gene resulting in misshapen haemoglobin
molecules, which in turn deforms red blood cells into a sickled shape. The
sickled red blood cells cause problems for two main reasons; they are easily
destroyed causing anaemia and related complications, and they cause
vaso-occlusion in many parts of the body producing painful symptoms and
eventual fatality. 

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