Sickle-cell disease
28657
226100825
2008-07-16T20:45:55Z
96.227.117.215
/* Signs and symptoms */
{{otheruses4|the disease itself|the genetic transmission of sickle-cell disease and its carrier state|sickle cell trait}}
{{DiseaseDisorder infobox |
Name = Sickle-cell disease|
Image = sicklecells.jpg |
Caption = Sickle-shaped red blood cells |
DiseasesDB = 12069 |
ICD10 = {{ICD10|D|57||d|55}} |
ICD9 = {{ICD9|282.6}} |
ICDO = |
OMIM = 603903 |
MedlinePlus = 000527 |
eMedicineSubj = med |
eMedicineTopic = 2126 |
eMedicine_mult = {{eMedicine2|oph|490}} {{eMedicine2|ped|2096}} {{eMedicine2|emerg|26}} {{eMedicine2|emerg|406}} |
MeshName = Sickle+Cell+anemia |
MeshNumber = C15.378.071.141.150.150 |
}}
'''Sickle-cell disease''' or '''sickle-cell anaemia''' (or '''anemia''') is a [[blood disorder]] characterized by [[red blood cell]]s that assume an abnormal, rigid, [[sickle]] shape. Sickling decreases the cells' flexibility and results in their restricted movement through [[blood vessel]]s, 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.<ref>{{cite journal |author=Platt OS, Brambilla DJ, Rosse WF, ''et al'' |title=Mortality in sickle cell disease. Life expectancy and risk factors for early death |journal=N. Engl. J. Med. |volume=330 |issue=23 |pages=1639–44 |year=1994 |month=June |pmid=7993409 |url=http://content.nejm.org/cgi/content/full/330/23/1639 |doi=10.1056/NEJM199406093302303}}</ref>
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 sickle red blood cells are not conducive to the parasites - in areas where malaria is common there is a [[Evolution|survival value]] in carrying the sickle-cell genes.
==Classification==
Sickle-cell anaemia is the name of a specific form of sickle-cell disease in which there is [[homozygote|homozygosity]] for the [[genetic mutation|mutation]] that causes HbS. Sickle-cell anaemia is also referred to as "HbSS", "SS disease", "haemoglobin S", or permutations thereof. Other, rarer forms of sickle-cell disease include sickle-[[haemoglobin C]] disease (HbSC), sickle beta-plus-[[thalassaemia]] (HbS/β<sup>+</sup>) and sickle beta-zero-thalassaemia (HbS/β<sup>0</sup>). These other forms of sickle-cell disease are [[compound heterozygous]] states in which the person has only one copy of the mutation that causes HbS and one copy of another abnormal [[haemoglobin]] [[allele]].
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]].
==Signs and symptoms==
Sickle-cell disease may lead to various acute and chronic complications, several of which are potentially lethal.
===Vaso-occlusive crisis===
The [[vaso-occlusive crisis]] is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ, resulting in [[ischemia]], [[pain]], and organ damage. The frequency, severity, and duration of these crises varies considerably. Painful crises are treated with hydration and analgesics; pain management requires [[opiate|opioid]] administration at regular intervals until the crisis has settled. For milder crises a subgroup of patients manage on [[NSAID]]s (such as [[diclofenac]] or [[naproxen]]). For more severe crises most patients require inpatient management for intravenous opioids; [[patient-controlled analgesia]] (PCA) devices are commonly used in this setting. [[Diphenhydramine]] is effective for the itching associated with the opioid use. Incentive spirometry, a technique to encourage deep breathing to minimise the development of [[atelectasis]], is recommended.
Because of its narrow vessels and function in clearing defective red blood cells, the [[spleen]] is frequently affected. It is usually [[infarction|infarcted]] before the end of childhood in individuals suffering from sickle-cell anaemia. This [[autosplenectomy]] increases the risk of infection from [[encapsulated organisms]];<ref>{{cite journal |author=Pearson H |title=Sickle cell anaemia and severe infections due to encapsulated bacteria |journal=J Infect Dis |volume=136 Suppl |issue= |pages=S25–30 |year= |pmid=330779}}</ref><ref>{{cite journal |author=Wong W, Powars D, Chan L, Hiti A, Johnson C, Overturf G |title=Polysaccharide encapsulated bacterial infection in sickle cell anaemia: a thirty year epidemiologic experience |journal=Am J Hematol |volume=39 |issue=3 |pages=176–82 |year=1992 |pmid=1546714 | doi = 10.1002/ajh.2830390305 <!--Retrieved from CrossRef by DOI bot-->}}</ref> 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.
===Other sickle-cell crises===
* ''Aplastic crises'' - are acute worsenings of the patient's baseline anaemia producing pallor, tachycardia, and fatigue. This crisis is triggered by [[parvovirus B19]], which directly affects [[erythropoiesis]] (production of red blood cells). Parvovirus infection nearly completely prevents red blood cell production for 2-3 days. In normal individuals this is of little consequence but the shortened red cell life of sickle-cell patients results in an abrupt, life-threatening situation. [[Reticulocyte]] counts drop dramatically during the disease and the rapid turnover of red cells leads to the drop in haemoglobin. Most patients can be managed supportively; some need blood transfusion.
* ''Splenic sequestration crises'' are acute, painful enlargements of the spleen. The abdomen becomes bloated and very hard. Management is supportive, sometimes with blood transfusion.
* ''Hemolytic crises'' are acute accelerated drop in haemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with co-existent [[G6PD deficiency]]. Management is supportive, sometimes with blood transfusion.
===Complications===
Sickle-cell anaemia can lead to various complications, including:
* [[Overwhelming post-splenectomy infection|Overwhelming post-(auto)splenectomy infection]] (OPSI) is due to functional asplenia, caused by encapsulated organisms such as ''[[Streptococcus pneumoniae]]'' and ''[[Haemophilus influenzae]]''. Daily [[penicillin]] prophylaxis is the most commonly used treatment during childhood with some haematologists continuing treatment indefinitely. Patients benefit today from routine vaccination for ''H. influenzae'', ''S. pneumoniae'' and ''Neisseria meningitidis''.
* [[Cerebrovascular accident|Stroke]] can result from a progressive vascular narrowing of blood vessels, preventing oxygen from reaching the [[human brain|brain]]. Cerebral infarction occurs in children, and cerebral hemorrhage in adults.
* [[Cholelithiasis]] and [[cholecystitis]] (gallstones) may result from excessive [[bilirubin]] production and precipitation due to prolonged [[haemolysis]].
* Avascular necrosis ([[aseptic bone necrosis]]) of the hip may occur as a result of ischemia.
* Decreased [[immune system|immune reactions]] due to [[hyposplenism]] (malfunctioning of the spleen)
* [[Priapism]] and [[infarction]] of the [[penis]].
* [[Osteomyelitis]] (bacterial bone infection) - [[Staphylococcus]] is the most common cause in the general populations; however, [[Salmonella]] is the most common causative organism in those individuals suffering from sickle-cell anemia.
* [[Opioid]] tolerance can occur as a normal, physiologic response to the therapeutic use of opiates. Addiction to opiates occurs no more commonly among individuals with sickle-cell disease than among other individuals treated with opiates for other reasons.
* [[Renal papillary necrosis|Acute papillary necrosis]] in the kidneys.
* Leg ulcers.
* In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages and retinal detachments can occur resulting in blindness. Regular annual eye checks are recommended.
* During pregnancy, [[intrauterine growth retardation]], spontaneous [[abortion]] and [[pre-eclampsia]] are the possibilities.
* Chronic pain: even in the absence of acute vaso-occlusive pain, many patients have chronic pain that is not reported<ref name="pmid18195334">{{cite journal |author=Smith WR, Penberthy LT, Bovbjerg VE, ''et al'' |title=Daily assessment of pain in adults with sickle cell disease |journal=Ann. Intern. Med. |volume=148 |issue=2 |pages=94–101 |year=2008 |pmid=18195334}}</ref>
* [[Pulmonary hypertension]] (increased pressure on the [[pulmonary artery]]), leading to strain on the [[right ventricle]] and a risk of [[heart failure]]; typical symptoms are shortness of breath, decreased exercise tolerance and episodes of [[syncope]]<ref name="pmid14985486">{{cite journal |author=Gladwin MT, Sachdev V, Jison ML, ''et al'' |title=Pulmonary hypertension as a risk factor for death in patients with sickle cell disease |journal=N. Engl. J. Med. |volume=350 |issue=9 |pages=886–95 |year=2004 |pmid=14985486 |doi=10.1056/NEJMoa035477|url=http://content.nejm.org/cgi/content/full/350/9/886}}</ref>
*Chronic renal failure - this develops in 4.2% and manifests itself with [[hypertension]] (high blood pressure), [[proteinuria]] (protein loss in the urine) and worsened anaemia. If it progresses to end-stage renal failure it carries a poor prognosis.<ref name="pmid1892333">{{cite journal |author=Powars DR, Elliott-Mills DD, Chan L, ''et al'' |title=Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality |journal=Ann. Intern. Med. |volume=115 |issue=8 |pages=614–20 |year=1991 |pmid=1892333}}</ref>
===Heterozygotes===
The heterozygous form (sickle cell trait) is almost always asymptomatic and the only significant manifestation is the renal concentrating defect presenting with [[isosthenuria]].
==Diagnosis==
In HbSS, the [[complete blood count|full blood count]] reveals [[haemoglobin]] levels in the range of 6-8 g/dL with a high [[reticulocyte]] count (as the bone marrow compensates for the destruction of sickle cells by producing more red blood cells). In other forms of sickle cell disease, Hb levels tend to be higher. A [[blood film]] may show features of [[hyposplenism]] ([[Codocyte|target cells]] and [[Howell-Jolly body|Howell-Jolly bodies]]).
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.<ref name="pmid10926923">{{cite journal |author=Clarke GM, Higgins TN |title=Laboratory investigation of hemoglobinopathies and thalassemias: review and update |journal=Clin. Chem. |volume=46 |issue=8 Pt 2 |pages=1284–90 |year=2000 |pmid=10926923 |doi= |url=http://www.clinchem.org/cgi/content/full/46/8/1284}}</ref>
==Pathophysiology==
Sickle-cell anaemia is caused by a [[point mutation]] in the β-globin chain of [[haemoglobin]], causing the amino acid [[glutamic acid]] to be replaced with the less polar amino acid [[valine]] at the sixth position. The β-globin gene is found on the short arm of [[chromosome 11]]. The association of two [[wild-type]] α-globin subunits with two mutant β-globin subunits forms haemoglobin S (HbS). Under low oxygen conditions, the absence of a polar amino acid at position six of the β-globin chain promotes the polymerisation of haemoglobin, which distorts red blood cells into a sickle shape and decreases their elasticity.
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]].
==Genetics==
[[Image:Sickle cell hemoglobin.png|right|thumb|A single amino acid change causes haemoglobin proteins to form fibers.]]
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.<ref name="pmid7505527">{{cite journal |author=Green NS, Fabry ME, Kaptue-Noche L, Nagel RL |title=Senegal haplotype is associated with higher HbF than Benin and Cameroon haplotypes in African children with sickle cell anemia |journal=Am. J. Hematol. |volume=44 |issue=2 |pages=145–6 |year=1993 |pmid=7505527 | doi = 10.1002/ajh.2830440214 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
In people [[heterozygous]] for HgbS ([[Genetic carrier|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 [[capillary|capillaries]]. Carriers only have symptoms if they are deprived of oxygen (for example, while climbing a mountain) or while severely [[dehydration|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.
[[Image:Sickle cell distribution.jpg|thumb|left|150px|Distribution of the sickle-cell trait shown in pink and purple]]
[[Image:Malaria distribution.jpg|thumb|left|150px|Distribution of [[malaria]] shown in green]]
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 structure|secondary]], [[tertiary structure|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 ''[[Genetic carrier|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 [[sickle cell trait|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 (biology)|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]].<ref name="pmid16001361">{{cite journal |author=Kwiatkowski DP |title=How malaria has affected the human genome and what human genetics can teach us about malaria |journal=Am. J. Hum. Genet. |volume=77 |issue=2 |pages=171–92 |year=2005 |pmid=16001361 |doi=10.1086/432519}} {{PMC|1224522}}</ref>
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 [[United States|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.
[[Image:Autorecessive.svg|right|thumb|200px|Sickle-cell disease is inherited in the autosomal recessive pattern.]]
===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 anaemia ("SS" in the diagram) and the other is Normal (AA), all of their children will have sickle-cell trait (AS).
# 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).
# 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 anaemia appears to be caused by a [[Dominance relationship#Recessive allele|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.
==Treatment==
===Painful (vaso-occlusive) crises===
Most people with sickle-cell disease have intensely painful episodes called ''vaso-occlusive crises''. The frequency, severity, and duration of these crises, however, vary tremendously. Painful crises are treated symptomatically with [[analgesic]]s; pain management requires [[opioid]] administration at regular intervals until the crisis has settled. For milder crises a subgroup of patients manage on [[NSAID]]s (such as [[diclofenac]] or [[naproxen]]). For more severe crises most patients require inpatient management for intravenous opioids; [[patient-controlled analgesia]] (PCA) devices are commonly used in this setting. [[Diphenhydramine]] is also an effective agent that is frequently prescribed by doctors in order to help control any itching associated with the use of opioids.
===Folic acid and penicillin===
Children born with sickle cell disease will undergo close observation by the pediatrician and will require management by a hemotologist to assure they remain healthy. These patients will take folic acid 1mg daily for life. From the age of birth to 5 years of age they will also have to take penicillin daily, due to the immature immune system which makes them more prone to early childhood illnesses.
===Acute chest crises===
Management is similar to vaso-occlusive crises with the addition of antibiotics (usually a quinolone or macrolide, since wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome),<ref>{{cite book | title=Pulmonary and Critical Care Medicine | editor=Bone RC et al., editors | author=Aldrich TK, Nagel RL. | chapter=Pulmonary Complications of Sickle Cell Disease. | edition=6th edition | date=1998 | pages=pp.1-10 | publisher=Mosby | location=St. Louis |isbn=0-81511-371-4}}</ref> oxygen supplementation for [[Hypoxia (medical)|hypoxia]], and close observation. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple [[blood transfusion]] or [[exchange transfusion]] is indicated. The latter involves the exchange of a significant portion of the patients red cell mass for normal red cells, which decreases the percent haemoglobin S in the patient's blood.
===Hydroxyurea===
The first approved drug for the causative treatment of sickle-cell anaemia, [[hydroxyurea]], was shown to decrease the number and severity of attacks in a study in 1995 (Charache ''et al'')<ref name="pmid7715639">{{cite journal |author=Charache S, Terrin ML, Moore RD, ''et al'' |title=Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia |journal=N. Engl. J. Med. |volume=332 |issue=20 |pages=1317–22 |year=1995 |pmid=7715639|doi= 10.1056/NEJM199505183322001}}</ref> and shown to possibly increase survival time in a study in 2003 (Steinberg ''et al'').<ref name="pmid12672732">{{cite journal |author=Steinberg MH, Barton F, Castro O, ''et al'' |title=Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment |journal=JAMA |volume=289 |issue=13 |pages=1645–51 |year=2003 |pmid=12672732 |doi=10.1001/jama.289.13.1645 |url=http://jama.ama-assn.org/cgi/content/full/289/13/1645}}</ref> This is achieved, in part, by reactivating [[fetal haemoglobin]] production in place of the haemoglobin S that causes sickle-cell anaemia. Hydroxyurea had previously been used as a [[chemotherapy]] agent, and there is some concern that long-term use may be harmful, but this risk has been shown to be either absent or very small and it is likely that the benefits outweigh the risks.<ref name=Platt2008>{{cite journal |author=Platt OS |title=Hydroxyurea for the treatment of sickle cell anemia |journal=N. Engl. J. Med. |volume=358 |issue=13 |pages=1362–9 |year=2008 |pmid=18367739 |doi=10.1056/NEJMct0708272}}</ref>
===Bone marrow transplants===
[[Bone marrow transplant]]s have proven to be effective in children.{{fact|date=April 2008}}
===Future treatments===
Various approaches are being sought for preventing sickling episodes as well as for the complications of sickle-cell disease. Other ways to modify hemoglobin switching are being investigated, including the use of [[phytochemicals]] such as [[nicosan]].
[[Gene therapy]] is under investigation.
==Situation of carriers==
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.
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.{{fact|date=April 2008}}
==History==
This collection of clinical findings was unknown until the explanation of the sickle cells in 1904 by the Chicago cardiologist and professor of medicine [[James B. Herrick]] (1861-1954) whose intern [[Ernest Edward Irons]] (1877-1959) found "peculiar elongated and sickle shaped" cells in the blood of Walter Clement Noel, a 20 year old first year dental student from Grenada after Noel was admitted to the Chicago Presbyterian Hospital in December [[1904]] suffering from [[anaemia]]. Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks". Noel completed his studies and returned to the capital of Grenada (St. George's) to practice [[dentistry]]. He died of [[pneumonia]] in [[1916]] and is buried in the Catholic cemetery at [[Sauteurs]] in the north of Grenada.<ref name="pmid2642320">{{cite journal |author=Savitt TL, Goldberg MF |title=Herrick's 1910 case report of sickle cell anemia. The rest of the story |journal=JAMA |volume=261 |issue=2 |pages=266–71 |year=1989 |pmid=2642320 | doi = 10.1001/jama.261.2.266 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
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.<ref>Konotey-Ahulu FID. Effect of environment on sickle cell disease in West Africa: epidemiologic and clinical considerations. In: Sickle Cell Disease, Diagnosis, Management, Education and Research. Abramson H, Bertles JF, Wethers DL, eds. CV Mosby Co, St. Louis. 1973; 20; cited in {{cite journal|last=Desai|first=D. V.|coauthors=Hiren Dhanani|year=2004|title=Sickle Cell Disease: History And Origin|url=http://www.ispub.com/ostia/index.php?xmlFilePath=journals/ijhe/vol1n2/sickle.xml|journal=The Internet Journal of Haematology|issn=1540-2649|volume=1|issue=2}}</ref> Also, the practice of using tar soap to cover blemishes caused by sickle-cell sores was prevalent in the African American community.{{fact|date=April 2008}}
[[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.<ref>{{cite journal|last=Desai|first=D. V.|coauthors=Hiren Dhanani|year=2004|title=Sickle Cell Disease: History And Origin| url=http://www.ispub.com/ostia/index.php?xmlFilePath=journals/ijhe/vol1n2/sickle.xml|journal=The Internet Journal of Haematology|issn=1540-2649|volume=1|issue=2}}</ref> These independent events occurred between 3,000 and 6,000 generations ago, approximately 70-150,000 years.
==Notes==
{{reflist|2}}
==Further reading==
*Chestnut, D. (1994). Perceptions of ethnic and cultural factors in the delivery of services in the treatment of sickle cell disease. Journal of Health and Social Policy, 5(3/4), 236.
*Jurmain, Bruce.; Lynn Kilgore, Wenda Trevathan (2005). ~~Introduction to Physical Anthropology~~. ISBN 0-495-18779-8
==External links==
* {{DMOZ|Health/Conditions_and_Diseases/Blood_Disorders/Sickle_Cell|Sickle cell}}
* {{DMOZ|Kids_and_Teens/Health/Conditions_and_Diseases/Sickle_Cell_Anemia/|Sickle cell (kids)}}
{{Hematology}}
[[Category:Blood disorders]]
[[Category:Genetic disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Health in Africa]]
[[Category:Pain]]
[[Category:Chronic pain syndromes]]
[[ar:فقر الدم المنجلي]]
[[bn:কাস্তে-কোষ ব্যাধি]]
[[de:Sichelzellenanämie]]
[[es:Anemia falciforme]]
[[eo:Serpoĉela anemio]]
[[fa:کمخونی داسیشکل]]
[[fr:Drépanocytose]]
[[ko:겸형 적혈구 빈혈증]]
[[id:Anemia sel sabit]]
[[it:Anemia drepanocitica]]
[[he:אנמיה חרמשית]]
[[nl:Sikkelcelanemie]]
[[ja:鎌状赤血球症]]
[[pms:Anemìa faussiforma]]
[[pl:Anemia sierpowata]]
[[pt:Anemia falciforme]]
[[ru:Серповидно-клеточная анемия]]
[[sl:Srpastocelična anemija]]
[[sr:Српаста анемија]]
[[fi:Sirppisoluanemia]]
[[sv:Sicklecellanemi]]
[[zh:鐮刀型紅血球疾病]]