Sickle Cell Disease (SCD) is a genetic disorder characterized by the presence of two copies of the sickle allele at one or both ends of chromosome 21. SCD affects approximately 1 in every 400 individuals worldwide. SCD is caused by mutations in the SLC24A5 gene, which encodes for a protein called sclerostin. Sickle cells are red blood cells with three copies of the sickle allele at their tips instead of four. These alleles result in hemoglobin deficiency, leading to anemia and low red blood cell mass. Hemolytic transfusion reactions occur when the patient’s body rejects the blood because it contains too much iron. Patients with SCD have a higher risk of developing thrombosis, pulmonary embolism, and other complications from blood transfusions than do non-scheduled carriers.
The most common symptom of SCD is anemia. Other symptoms include fatigue, pain in joints and muscles, shortness of breath, weakness and numbness in fingers or toes.
Sickle cell disease can be diagnosed during pregnancy by amniocentesis and chorionic villus sampling. If the fetus is found to have two sickle cell alleles or is a carrier of the allele, the chances are extremely low (one in four) that a child will also inherit the disease. If both parents are carriers, the probability increases to one in two.
If the child does not inherit SCD from his parents, he is called a ‘true carrier’ and does not develop the disease.
Carriers of sickle cell disease are at increased risk for various types of cancers, kidney failure and stroke. These complications are believed to be proportional to the percentage of red blood cells that contain mutated hemoglobin (HbS).
Sickle cell disease causes anemia by the lost of a large number of red blood cells. This reduces the rate at which oxygen can be delivered around the body. This in turn causes physical symptoms such as breathlessness and fatigue.
It can also cause complications such as organ failure and strokes.
The most important treatment of sickle cell disease is pain relief. People with sickle cell disease are susceptible to episodes of severe pain in their bones and other organs. No medication can completely eliminate these episodes.
People with the disease can be treated with painkillers and narcotics to relieve the pain. They can also be given an injection of the drug erythropoietin, which reduces the severity and frequency of the painful attacks.
Blood transfusions are often used to treat people with sickle cell disease who are suffering from extreme fatigue, shortness of breath or severe anemia. The transfusions work because the diseased cells are less sticky than normal red blood cells, so they are unable to stick to the inside of blood vessels. However, due to the increased risk of blood clots and other complications, a person with SCD should only receive transfusions in a medical setting.
In addition, they are more likely to develop antibodies against foreign tissue, which can cause future transfusions to be ineffective.
People with sickle cell disease are less able to fight off infection than people without the disease. This is mainly due to two factors: the anemia and the frequent infections that result from damaged blood vessels. Because of this, people with SCD should be vaccinated against influenza, pneumococcus and hepatitis.
Both prenatal and genetic counseling are recommended for people with sickle cell disease. Prenatal counseling is important to ensure that children with the disease are diagnosed at birth and begin receiving proper treatments. Genetic counseling helps people make informed decisions about their sexual activity.
Couples where both partners are carriers of the mutated HbS allele have a one in two chance each time they have a child that the baby will inherit two copies of the allele and therefore develop sickle cell disease.
New research has shown that thalidomide and pentoxifylline may be able to correct the effects of mutated HbS in adults with sickle cell disease.
A bone marrow transplant can cure people with two copies of the HbS allele. A person with the disease can use a relative as a donor, but this procedure is still relatively new and risky.
Cancer, especially leukemia, is a serious risk in people with sickle cell disease. Cancer is caused by the organ damage that the disease causes. Smoking greatly increases the risk, and people with sickle cell disease are advised to stop smoking if they wish to reduce their cancer risk.
The earliest known written record of sickle cell anemia dates from 450 BC, when Hippocrates described a condition in which “the seed [sperm] … is rotten”.
The condition was found in malaria victims, who had a higher concentration of the abnormal haemoglobin.
The sickle cell gene was first described by J. Van Wyk and E. Erasmus in 1901 at the University of Stellenbosch, in Cape Town, South Africa.
They found that children with a rare blood disorder that causes paleness, weakness and breathing difficulties are often stillborn or die soon after birth. Subsequent studies showed this condition to be the result of a mutation in the β-globin gene.
The first person with the disease was described by James Leonard Holland in 1902, an American doctor working in Turkey. A young patient of his, named Najeeb, had “thin pale blood” and occasionally hemorrhaged after minimal trauma. It was later established that this patient had three copies of the gene that causes sickle cell disease.
Later work showed that the frequency of the disease varies across the world, with people in Africa having the highest frequencies. In some parts of this continent it is so common that up to 46% of the population carry the gene. The disease is most commonly found in places where malaria is or was common.
This suggests that the gene confers a survival advantage against malaria and that the disease itself is a result of balancing selection.
Sickle cell disease is named after the characteristic sickle-shaped (crescent) red blood cells (erythrocytes) that are found in patients with the condition. These sickle shaped cells are less able to travel through small blood vessels and capillaries than normal red blood cells, which can lead to a blockage. This blockage can cause a back-up of blood, causing tissue death in organs and other parts of the body.
The name “sickle cell” can refer to the individual disease (also known as sickle cell anaemia), or to the underlying genetic condition causing it. The condition is typically classified into three types:
The symptoms and severity of sickle cell disease type vary greatly between individual patients, with some people experiencing few problems throughout their life and others dying from the condition in childhood. The different types have been identified to help doctors predict the risks and develop an effective treatment plan for each patient. Most of the time, having just one sickle cell gene does not cause any problems; it is when a person has two copies of the gene that affects health.
The sickle cell disease is most common in people with ancestors from parts of the world where malaria used to be common, including areas in the Mediterranean, West Africa, India, South Central States and Arabia. It is most commonly found in humans with ancestors from Nigeria, Cameroon, Central African Republic and Senegal.
In sickle cell anaemia, one copy of the gene that causes haemoglobin to be made as a beta-globin instead of the usual alpha-globin is enough to cause the disease. There are two main types of sickle cell anaemia:
There are also several other less common types.
In sickle cell trait, one copy of the gene that causes haemoglobin to be made as a beta-globin instead of the usual alpha-globin is enough to cause the trait. The trait does not usually cause any problems but in certain circumstances it can lead to a condition known as exercise induced asthma. This happens when the deformed haemoglobin (shaped like a sickle) gets stuck in blood vessels and stops them from expanding andcontracting properly.
This causes the airways to become narrower so it is more difficult to breathe.
The symptoms of sickle cell disease include:
A few patients also experience pain in their bones ( osteomalacia) due to lack of blood flow.
Sickle cell crises usually occur within the first ten years of life and often lead to an early death before the patient reaches adulthood.
The level of oxygen in the blood has a direct effect on the stability of the haemoglobin molecules. When the concentration of haemoglobin is high (as in the lungs) the haemoglobin is more stable; when it is low (as in muscle tissue during strenuous exercise), the haemoglobin is less stable. The shape of the haemoglobin molecule also affects how easily it can combine with oxygen.
Normally the difference in oxygen concentration between the lungs and muscle tissue is enough to keep the unstable haemoglobin stable.
If a person has SS disease with a high concentration of haemoglobin in their body, this may be enough to keep the haemoglobin stable even during strenuous exercise. This explains why many patients report that their symptoms get worse with physical exercise. When haemoglobin is combined with oxygen it has a rigid, unchanging shape.
De-oxygenated haemoglobin (that is, haemoglobin without oxygen) is slightly different; it has a slight bend near the middle of the molecule. This bend makes de-oxygenated haemoglobin slightly more unstable, so it is more likely to readily release oxygen to areas where it is in high demand, such as muscle tissue.
Hemoglobin also has an affinity to carbon monoxide, a poisonous gas that competes with oxygen for the red blood cell’s haemoglobin. The sickling process gives the de-oxygenated haemoglobin a similar rigid, unchanging shape so that it is more likely to readily absorb the carbon monoxide instead of oxygen. This can be very dangerous because the person may be deprived of essential oxygen.
There are three main types of thalassemia:
Most forms of thalassemia are due to inherited mutations in one of the four genes that code for the subunits of haemoglobin. These genes are known as “ß-globin”, “Delta-globin” (which has three variants: Delta-zero, Delta-one and Delta-two), “Epsilon-globin” and “Gamy-globin”.
The normal rule for these four genes is that you need two copies of each one in order to produce healthy haemoglobin, one copy of each for reduced function, and only one functional “ß-globin” gene for production of gamma-globin.
Haemoglobin ß is found in all red blood cells and contributes to their overall shape and function. People with ß-thalassemia inherit mutated copies of the “ß-globin” gene, which reduces the production of haemoglobin ß and results in smaller, less resilient red blood cells. The bones, spleen and liver are most often affected by the impaired red blood cell production.
People with severe forms of ß-thalassemia may experience mild to severe anemia. Haemoglobin E (ß(E)) is a normal variant of haemoglobin, commonly found in people from Southeast Asia. People with this condition inherit a single copy of the mutated “ß-globin” gene that codes for haemoglobin ß(E).
They experience some symptoms similar to those of ß-thalassemia, such as mild to moderate anemia and occasional spleen damage.
Haemoglobin E (ß(E)) can cause false positive test for ß-thalassemia when the molecular blood test is used.
The other genes, “Delta-globin”, “Epsilon-globin” and “Gamy-globin”, all code for proteins that assist in the process of producing haemoglobin ß. Mutations of any of these genes can cause a decrease in the amount of haemoglobin ß made, causing the disease known as thalassemia minor.
Examination of the amount of haemoglobin in red blood cells gives a rough indication of the extent of the condition.
In general, thalassemias are most easily treated during childhood, when medical treatment is more effective and growth has not yet been severely affected.
These treatments need to be continued throughout the patient’s life, since these are recurring diseases.
The most common and effective treatment for thalassemia is regular blood transfusions, which increases the amount of haemoglobin in the blood. Blood transfusions can improve the symptoms of thalassemia minor by increasing the amount of haemoglobin in the body and relieving some of the symptoms.
Blood transfusions are not effective on thalassemia major since the bone marrow is damaged in that condition, and cannot produce normal red blood cells.
The best way to avoid the dangers of thalassemia is to seek early diagnosis and start a lifelong treatment plan as soon as possible. The main form of treatment is regular blood transfusions, as well as iron chelation drugs to remove excess iron from the body. Other forms of treatment include bone marrow transplants and enzyme therapies.
Without proper treatment, most people with thalassemia experience shortened life spans.
In recent years, doctors and researchers have made some progress in treating thalassemia.
Extracorporeal photopheresis (ECP) is a procedure that removes the defective blood cells from the patient’s blood, treats the blood with UV light to kill viruses and bacteria, and then returns the treated blood back into the body.
In 2003, researchers at the University of Minnesota developed a method of treating thalassemia by removing the defective fetal hemoglobin genes and replacing them with healthy adult hemoglobin genes. This method is not yet widely available to patients, but it has shown promise in early testing.
Until recently, bone marrow transplants had a high failure rate and were not recommended as a treatment for thalassemia. Recent advances in medicine have made this a more viable option.
Gene therapy is showing promise in animal testing. In theory, it would work by giving the patient a virus that has had the defective “ß-globin” genes removed and then replaced with healthy adult “ß-globin” genes.
Researchers are also attempting to use a recombinant adenovirus vector to deliver the normal fetal haemoglobin gene directly to the patient’s bone marrow cells. This would allow the patient’s own bone marrow to begin producing normal fetal haemoglobin, which would stop the need for regular blood transfusions.
Bone marrow transplants offer a possible cure for thalassemia major, but patients need to find a matching donor that is a close genetic match.
Without a close match, patients are at risk of rejecting the donated bone marrow.
There are also certain drugs that can be used to help the patient’s body accept the donated bone marrow.
The thalassemias are the topic of much research, as scientists seek to better understand and treat the diseases.
Recent research has focused on finding a cure for thalassemia major, which is fatal without regular blood transfusions.
Bone marrow transplants are the current treatment of choice for thalassemia major.
It was discovered in the late 1960s that thalassemia resulted from deletions in the alpha globin gene cluster (“HBA2”) on chromosome 16.
Later research, starting in the early 1980s, isolated the precise point of the deletions: aA~T (HBA1).
Also during this time, researchers found that a single base pair substitution in the “HBB” gene results in the most common form of thalassemia.
This substitution, C to T (HBB), is the reason for the name “thalassemia,” which comes from the Greek words “thalasso” (“copper”), and “haima” (“blood”).
Sources & references used in this article:
A rapid diagnostic test for sickle cell anemia by HA Itano, L Pauling – Blood, 1949 – pdfs.semanticscholar.org
TCD in sickle cell disease: an important and useful test by RJ Adams – Pediatric radiology, 2005 – Springer
A sensitive new prenatal test for sickle-cell anemia by JC Chang, YW Kan – New England Journal of Medicine, 1982 – Mass Medical Soc
A simple, rapid, low-cost diagnostic test for sickle cell disease by X Yang, J Kanter, NZ Piety, MS Benton, SM Vignes… – Lab on a Chip, 2013 – pubs.rsc.org
A rapid whole blood solubility test to differentiate the sickle-cell trait from sickle-cell anaemia by RG Huntsman, GPT Barclay, DM Canning… – Journal of clinical …, 1970 – jcp.bmj.com
Diagnostic test for sickle-cell by E Shanbrom, A Louderback – US Patent 3,847,545, 1974 – Google Patents
Prenatal diagnosis of sickle cell anemia by restriction and endonuclease analysis: HindIII polymorphisms in gamma-globin genes extend test applicability by JA Phillips, SR Panny, HH Kazazian… – Proceedings of the …, 1980 – National Acad Sciences
Studies on abnormal hemoglobins: I. Their demonstration in sickle cell anemia and other hematologic disorders by means of alkali denaturation by K Singer, AI Chernoff, L Singer – Blood, 1951 – ashpublications.org