Genetic Disorder: Sickle Cell Anemia
Introduction:
What Are Genetic Disorders?
Genes are the instructions for making proteins. Proteins are very important as they do most of the functions in a cell such as building structures and breakdown toxins. Genetic disorders are diseases that are caused by a change in the structure or sequence of a gene in the DNA sequence causing it to be away from the normal sequence. Hence, causing the protein to malfunction or missing entirely. This condition medical condition is called a genetic disorder.
There are 2 types of mutation:
- Gene or point mutation. This happens when there is a change in the nucleotide base sequence of the DNA molecule in a gene. For example, sickle cell anemia, phenylketonuria, and Tay-Sachs disease.
- Chromosomal mutation or aberration. This happens when there is a change in the amount and arrangement of the DNA. For example, Down syndrome, Klinefelter syndrome, and Turner syndrome.
In this assignment, I will be focusing on sickle cell anemia which is a genetic disorder which is caused by gene mutation when base substitution happens.
What Is Base Substitution?
Base substitution happens when one nucleotide is swapped with a different nucleotide during DNA replication. For example, ATT is changed to ATC when a thymine nucleotide is replaced with a cytosine nucleotide. Only a single nucleotide within a gene sequence is changed, hence only one codon is affected. A codon is 3 bases that are read for amino acid sequence. Although it alters only a single codon in a gene, it still greatly impacts protein production.
Base substitution can lead to three different subcategories of mutations:
- Missense mutation. This mutation alters the codon which results in producing incorrect or different amino acids during translation. This lead to the activity of the enzyme or hormone produced might be decreased or destroyed.
- Nonsense mutation. This mutation alters the codon to become a stop codon which prematurely terminates the synthesis of a protein molecule. This results in the destruction of the function of the gene product.
- Silent mutation. This mutation alters the codon but not the encoded amino acid, thus the same amino acid is translated. Therefore, there is no change in the product, and is undetectable without sequencing the gene.
Besides base substitution, gene mutation can also occur when there is a base insertion, base deletion, and base inversion. These are the different types of gene mutation.
Gene mutation can be caused by a spontaneous mutation which is the occurrence of mutation randomly and spontaneously without any known cause. Besides that, it can also happen due to the exposure of DNA to chemical agents or various type of radiation that causes changes in DNA. For sickle cell anemia, it is caused by spontaneous mutation as the mutagens that induced the change in DNA is unknown.
Pathophysiology of Sickle Cell Anaemia
Definition of Pathophysiology
Pathophysiology is the combination of pathology (the study of the causes and complications of the disease) and physiology (the study of functions and mechanisms in a living system). Thus, the pathophysiology is the study of the disordered physiological mechanisms that induce disease or damage, resulting from it, or are otherwise associated with it. Hence, it aims to uncover the functional modifications that arise due to a disorder or pathological state within an organism.
What Is Sickle Cell Anaemia?
The central pathophysiology of sickle cell anemia is the loss of red blood cell elasticity. Regular red blood cells are very elastic and have a biconcave disc structure that helps the cells to move through capillaries to deform and transport oxygen efficiently. Low oxygen tension in sickle cell disease promotes the sickling of red blood cells and frequent sickling destroys the cell membrane and reduces the elasticity of the cell. As normal oxygen tension is restored, these cells struggle to return to a normal structure. As a result, as they pass through small capillaries, these stiff blood cells are unable to deform, leading to artery blockage and ischemia which is a condition where the blood flow is restricted. Even though the bone marrow tries to compensate by producing new red blood cells, it does not equal the rate of damage. Usually, normal red blood cells survive for 90-120 days, but sickled cells’ lifespan is just 10-20 days.
Sickle cell anemia is the most common type of sickle cell disease. It results in an abnormality in the oxygen-carrying protein called hemoglobin found in the red blood cells. The shape of the red blood cells was originally smooth, biconcave disc-shaped but when someone has sickle cell anemia, the shape of the red blood cell becomes crescent-shaped. This causes the red blood cell to have a rigid sickle shape and the red blood cell loses its elasticity. This lowers the ability of the blood to carry oxygen and shortened the red blood cell lifespan, hence causing shortness of breath, weakness, feeling tired, and a poor ability to exercise. Sickle cell anemia is an inherited disorder in an autosomal recessive pattern from parents.
What Causes Sickle Cell Anaemia?
Mutation in the haemoglobin-Beta gene located on chromosome 11 causes sickle cell disease. In the beta-hemoglobin gene, a single-point mutation (missense mutation) that transforms a GAG codon into a GUG codon when transcribed, which encodes the amino acid valine rather than the glutamic acid. This is due to, the T base in the normal DNA codon CTT is substituted with the A base causing the DNA codon to be abnormal, CAT. Hence, hemoglobin S (HbS) is produced instead of the normal hemoglobin A (HbA).
Two copies of the hemoglobin gene are essential to everyone; one from their mother and one from their father. If one of these genes carries the instructions for the production of sickle hemoglobin (HbS) and the other carries the instructions for the production of normal hemoglobin (HbA), then the individual has the Sickle Cell Trait and is a sickle hemoglobin gene carrier. This means that in their red blood cells, this person has enough healthy hemoglobin to keep the cells elastic and they do not have the signs of sickle cell disorders.
If both copies of the hemoglobin gene hold information for producing sickle hemoglobin, thus this may be the only form of hemoglobin they may manufacture and sickled cells maybe produced.
Symptoms
ANAEMIA: Sickle cells easily break away and die, leaving very few red blood cells in your body. Typically, red blood cells survive for about 120 days before they need to be replaced. Yet sickle cells typically die within 10 to 20 days, leaving a red blood cell deficit (anemia). Your body does not get enough oxygen without enough red blood cells, inducing fatigue.
PAIN EPISODES: A significant sign of sickle cell anemia is periodical episodes of pain, called pain crises. When sickle-shaped red blood cells block the blood supply to your lung, abdomen, and joints through small blood vessels, pain occurs. Pain can happen in your bones as well. There is also chronic discomfort in some teenagers and adults with sickle cell anemia, which may result from damage to bones and limbs, ulcers, and other causes.
SWELLING OF HANDS AND FEET: Swellings are caused by sickle-shaped red blood cells that obstructs blood flow to the hands and feet.
FREQUENT INFECTIONS: Sickle cells can cause spleen damage, causing you more susceptible to infections. Doctors typically provide vaccines and antibiotics to babies and children with sickle cell anemia to prevent potentially lethal infections, such as pneumonia.
DELAYED GROWTH OR PUBERTY: The oxygen and nutrients required for development are supplied to your body by red blood cells. In babies and children, an inadequacy of healthy red blood cells will hinder development and delay puberty in adolescents.
VISION PROBLEMS: Sickle cells can be plugged into tiny blood vessels which supply your eyes. This can harm the retina, the part of the eye that conducts visual signals and pose a problem with vision.
Complications Caused by Sickle Cell Anaemia
A number of complications can be caused by sickle cell anemia namely, stroke, acute chest syndrome, pulmonary hypertension, organ damage, blindness, leg ulcers, gallstones, priapism, and pregnancy complications.
First, stroke. This can occur when sickle cells obstruct the flow of blood to your brain region. Stroke symptoms include seizures, arm and leg stiffness or numbness, abrupt speech disturbances, and losing consciousness. If any of these signs and symptoms are present in your child, get medical attention right away. A stroke can be lethal.
The second is acute chest syndrome. This life-threatening condition may be caused by a lung infection or sickle cells blocking blood vessels in the lungs, resulting in chest pain, fever, and struggle in breathing. It might need urgent medical treatment.
Third, pulmonary hypertension. In the lungs of individuals with sickle cell anemia may have elevated blood pressure. This complication impacts adults typically. Widely known signs of this disorder include shortness of breath and fatigue, which can be lethal.
Fourth, is organ damage. Sickle cells that block the blood supply to organs deprive blood and oxygen from the affected organs. Blood is also extremely deficient in oxygen in sickle cell anemia. This shortage of oxygen-rich blood, in organs including kidneys, liver, and spleen, can destroy these organs and nerves and can be lethal.
Fifth is blindness. Small blood vessels that supply the eyes can be blocked by sickle cells. This will harm the eye over time, and cause blindness.
Sixth, leg ulcers. Sickle cell anemia can cause your legs to have open wounds.
Seventh, gallstones. A substance called bilirubin is formed through the decomposition of red blood cells. In your body, a high concentration of bilirubin may lead to gallstones.
Eighth, priapism. Men with sickle cell anemia may have painful, long-lasting erections in this state. Sickle cells, which can contribute to impotence over time, can obstruct the blood vessels in the penis.
Lastly, pregnancy complications. Sickle cell anemia can raise the risk of high blood pressure and blood clots during pregnancy. The risk of miscarriage, premature labor, and low birth weight of babies may also be increased.
Diagnosis of Sickle Cell Anaemia
The defective sickle cell hemoglobin can be detected through a blood test. A blood sample is drawn from a vein in the arm in adults. The blood sample is typically obtained from a finger or heel in small children and infants. The sample is then sent to a laboratory where the defective hemoglobin is screened for.
By adding sodium metabisulfite, the sickling of red blood cells on a blood film can be induced. It is also possible to demonstrate the presence of sickle hemoglobin with the ‘sickle solubility test’. In a reduction solution (such as sodium dithionite), a mixture of hemoglobin S (HbS) gives a cloudy and opaque appearance, whereas normal hemoglobin (HbA) gives a clear solution.
In hemoglobin electrophoresis, a process of gel electrophoresis is done in which different types of hemoglobin travel at differing rates, and irregular hemoglobin forms can be identified. From there, sickle cell hemoglobin (HbS) can be recognized. It is possible to verify the diagnosis with high-performance liquid chromatography. Genetic testing is seldom conducted since it is highly specific for sickle cell hemoglobin (HbS).
Before having babies, people who are identified carriers of the disease typically seek genetic counseling. Taking either a blood sample from the fetus or a sample of amniotic fluid - through amniocentesis or chorionic villi sampling - is a procedure to see whether an unborn child has the disorder. As there are higher risks when taking a blood sample from a fetus, the latter test is often chosen.
