Sickle-cell disease or sickle-cell anaemia (or anemia) is a blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in their restricted movement through blood vessels, depriving downstream tissues of oxygen. The disease is chronic and lifelong: individuals are most often well, but their lives are punctuated by periodic painful attacks and a risk of various other complications. Life expectancy is shortened, with older studies reporting an average life expectancy of 42 and 48 years for males and females, respectively.
Sickle-cell disease occurs more commonly in people (or their descendants) from parts of 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 sickle 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 term "disease" is applied since the inherited abnormality causes a pathological condition that can lead to death and severe complications. Not all inherited variants of haemoglobin are detrimental, a concept known as genetic polymorphism.
Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected. It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anaemia. This autosplenectomy increases the risk of infection from encapsulated organisms; preventive antibiotics and vaccinations are recommended for those with such asplenia.
A recognised type of sickle crisis is the acute chest syndrome, a condition characterised by fever, chest pain, difficulty breathing, and pulmonary infiltrate on a chest X-ray. Given that pneumonia and sickling in the lung can both produce these symptoms, the patient is treated for both conditions. It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.
Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test". A mixture of haemoglobin S (Hb S) in a reducing solution (such as sodium dithionite) gives a turbid appearance while normal Hb gives a clear solution.
Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speed. Sickle-cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high performance liquid chromatography (HPLC). Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.
The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease. Normal red blood cells are quite elastic, which allows the cells to deform to pass through capillaries. In sickle-cell disease, low oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. Consequently, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.
Sickle cell gene mutation probably arose spontaneously in different geographic areas as suggested by restriction endonuclease analysis. These clinically important variants are known as Cameroon, Senegal, Benin, Bantu and Saudi-Asian. Their clinical importance springs from the fact that some of them are associated with higher HbF levels e.g Senegal and Saudi-Asian variants, and tend to have milder disease.
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 its structure and function.
The gene defect is a known mutation of a single nucleotide (see single nucleotide polymorphism - SNP) (A to T) of the β-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 associate with 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 disease 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 disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India and the Middle East.
The Price equation is a simplified mathematical model of the genetic evolution of sickle-cell anaemia.
The malaria parasite has a complex life cycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cell to rupture, making the plasmodium unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle-cell trait (selection for the heterozygote).
In the USA, where there is no endemic malaria, the prevalence of sickle-cell anaemia amongst African Americans is lower (about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria from Africa, the condition is purely disadvantageous, and will tend to be bred out of the affected population.
Sickle-cell anaemia 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.
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.
After the mutation responsible for this disease was discovered in 1979, the U.S. Air Force required African American applicants to test for the mutation. It dismissed 143 applicants because they were carriers, even though none of them had the condition. It eventually withdrew the requirement, but only after a trainee filed a lawsuit.
The disease was named "sickle-cell anaemia" by Vernon Mason in 1922. In retrospect some elements of the disease had been recognized earlier: a paper in the Southern Journal of Medical Pharmacology in 1846 described the absence of a spleen in the autopsy of a runaway slave. The African medical literature reported this condition in the 1870s where it was known locally as ogbanjes ("children who come and go") because of the very high infant mortality rate caused by this condition. A history of the condition tracked reports back to 1670 in one Ghanaian family. Also, the practice of using tar soap to cover blemishes caused by sickle-cell sores was prevalent in the African American community.
Linus Pauling and colleagues were the first, in 1949, to demonstrate that sickle cell disease occurs as a result of an abnormality in the haemoglobin molecule. This was the first time a genetic disease was linked to a mutation of a specific protein, a milestone in the history of molecular biology.
The origin of the mutation that led to the sickle-cell gene was initially thought to be in the Arabian peninsula, spreading to Asia and Africa. It is now known, from evaluation of chromosome structures, that there have been at least four independent mutational events, three in Africa and a fourth in either Saudi Arabia or central India. These independent events occurred between 3,000 and 6,000 generations ago, approximately 70-150,000 years.
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