View source for Sickle cell disease

{{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        = Normal and 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 '''drepanocytosis'''), is a life-long [[blood disorder]] characterized by [[red blood cell]]s that assume an abnormal, rigid, [[sickle]] shape. Sickling decreases the cells' flexibility and results in a risk of various complications. The sickling occurs because of a [[mutation]] in the [[hemoglobin]] [[gene]]. Life expectancy is shortened, with 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 |issn=0028-4793}}</ref>

Sickle-cell disease, usually presenting in childhood, occurs more commonly in people (or their descendants) from parts of [[tropical]] and [[sub-tropical]] regions where [[malaria]] is or was common. One-third of all [[Indigenous peoples|indigenous]] inhabitants of [[Sub-Saharan Africa]] carry the gene<ref>[http://sicklecell.md Sicklecell.md]</ref>, because in areas where malaria is common, there is a [[Evolution|survival value]] in carrying only a single sickle-cell gene ([[sickle cell trait]]).<ref>[http://sicklecell.md/faq.asp#q1 Sicklecell.md FAQ]: "Why is Sickle Cell Anaemia only found in Black people?</ref> Those with only one of the two [[alleles]] of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria plasmodium is halted by the sickling of the cells which it infests. 

The prevalence of the disease in the [[United States]] is approximately 1 in 5,000, mostly affecting Americans of Sub-Saharan African descent, according to the [[National Institutes of Health]].<ref>http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_Summary.html</ref>  In the United States, about 1 in 500 black births have sickle-cell anemia.

==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. In [[heterozygous]] people, who have only one sickle gene and one normal adult hemoglobin gene, it is referred to as "HbAS" or "sickle cell trait".  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, because 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 meow


[[hello]].

Balls.

==Diagnosis==
In HbSS, the [[complete blood count|full blood count]] reveals [[haemoglobin]] levels in the range of 6–8&nbsp;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, whereas 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 speeds. 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 |month=Aug |issn=0009-9147}}</ref>

An acute sickle-cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an [[occult]] urinary tract infection, and chest X-ray to look for occult pneumonia should be routinely performed.<ref>{{cite web |url=http://www.bestbets.org/bets/bet.php?id=1102 |title=BestBets: Does routine urinalysis and chest radiography detect occult bacterial infection in sickle cell patients presenting to the accident and emergency department with painful crisis? |format= |work= |accessdate=}}</ref>

==Pathophysiology==
Sickle-cell anaemia is caused by a [[point mutation]] in the β-globin chain of [[haemoglobin]], causing the hydrophilic amino acid [[glutamic acid]] to be replaced with the hydrophobic 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 (being at high altitude, for example), the absence of a polar amino acid at position six of the β-globin chain promotes the non-covalent polymerisation (aggregation) 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. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and [[ischaemia]].

The actual anemia of the illness is caused by [[hemolysis]], the destruction of the red cells inside the spleen, because of their misshape.  Although the [[bone marrow]] attempts to compensate by creating new red cells, it does not match the rate of destruction.<ref>http://sickle.bwh.harvard.edu/scd_background.html</ref> Healthy red blood cells typically live 90-120 days, but sickle cells only survive 10–20 days.<ref>http://emedicine.medscape.com/article/778971-overview</ref>

==Genetics==
[[Image:Sickle cell haemoglobin.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 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 |month=Oct |issn=0361-8609 |url=http://www.nlm.nih.gov/medlineplus/sicklecellanemia.html |format=Free full text}}</ref>

In people [[heterozygous]] for HgbS ([[Genetic carrier|carriers]] of sickling haemoglobin), the polymerisation problems are minor, because the normal [[allele]] is able to produce over 50% of the haemoglobin. 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 have symptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severely [[dehydration|dehydrated]]. Under normal circumstances, these painful crises occur 0.8 times per year per patient.{{Fact|date=November 2008}}  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|Historical distribution of [[malaria]] (no longer endemic in Europe) shown in green]]
[[Image:Paludisme - Frequence statistique.png|thumb|left|150px|Modern distribution of malaria]]
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]] being 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 GTG [[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 in conditions of normal [[oxygen]] concentration. 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 [[autosome|autosomal]] [[incomplete dominance|incomplete dominant]] and can be found on the short arm of chromosome 11. A person that receives the defective gene from both father and mother develops the disease; a person that 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's developing the disease and a 1-in-2 chance of their child's being just a carrier.  Since the [[sickle cell trait|gene]] is incompletely recessive, carriers can produce a few sickled red blood cells, 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 adaptive 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 |month=Aug |issn=0002-9297}} {{PMC|1224522}}</ref>  Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.<ref>http://www.cdc.gov/ncidod/EID/vol7no6/romi.htm</ref><ref>http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1808464</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 cells with defective haemoglobin to rupture prematurely, 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 among blacks is lower (about 0.25%) than in [[West Africa]] (about 4.0%) and is falling. Without endemic malaria from Africa, the sickle cell mutation is purely disadvantageous and will tend to be selected out of the affected population. Another factor limiting the spread of sickle-cell genes in North America is the absence of cultural proclivities to polygamy. <ref>http://journals.cambridge.org/action/displayAbstract?aid=1361276</ref>

[[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 on what haemoglobin genes are inherited from his parents. 
# If one parent has sickle-cell anaemia (SS) and the other has sickle-cell trait (AS), there is a 50% chance of a child's having sickle-cell disease (SS) and a 50% chance of a child's having sickle-cell trait (AS). 
# When both parents have sickle-cell trait (AS), a child has a 25% chance (1 of 4) of sickle-cell disease (SS), as shown in the diagram.

==Treatment==
===Cyanate===
Dietary cyanate, from foods containing cyanide derivatives, has been used as a treatment for sickle- cell anemia.<ref>http://www.clarafelixclinic.org/assets/further_info/cyanate_houston.pdf</ref> In the laboratory, cyanate and thiocyanate irreversibly inhibit sickling of red blood cells drawn from sickle cell anemia patients.<ref>http://www.clarafelixclinic.org/assets/further_info/thiocyanate_agbai.pdf</ref> However, the cyanate would have to be administered to the patient for a lifetime, as each new red blood cell created must be prevented from sickling at the time of creation. Cyanate also would be expelled via the urea of a patient every cycle of treatment.  Also see [[nicosan]].

===Painful (vaso-occlusive) crisis===
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 hematologist to assure they remain healthy. These patients will take a 1&nbsp;mg dose of folic acid daily for life. From birth to five years of age, they will also have to take penicillin daily due to the immature immune system that makes them more prone to early childhood illnesses.

===Acute chest crisis===
Management is similar to vaso-occlusive crisis, 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=      C et al., editors | author=Aldrich TK, Nagel RL. | chapter=Pulmonary Complications of Sickle Cell Disease. | edition=6th | 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 of 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 |month=May |issn=0028-4793}}</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 |month=Apr |last12=Ramirez |first12=G |last13=Adler |first13=B |last14=Smith |first14=W |last15=Carlos |first15=T |last16=Ataga |first16=K |last17=Decastro |first17=L |last18=Bigelow |first18=C |last19=Saunthararajah |first19=Y |last20=Telfer |first20=M |last21=Vichinsky |first21=E |last22=Claster |first22=S |last23=Shurin |first23=S |last24=Bridges |first24=K |last25=Waclawiw |first25=M |last26=Bonds |first26=D |last27=Terrin |first27=M |issn=0098-7484}}</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 |month=Mar |issn=0028-4793}}</ref>

===Bone marrow transplants===
[[Bone marrow transplant]]s have proven to be effective in children.<ref name="pmid8663884">{{cite journal |author=Walters MC, Patience M, Leisenring W, ''et al.'' |title=Bone marrow transplantation for sickle cell disease |journal=N. Engl. J. Med. |volume=335 |issue=6 |pages=369–76 |year=1996 |month=August |pmid=8663884 |doi= 10.1056/NEJM199608083350601|url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=8663884&promo=ONFLNS19 |last12=Sullivan |first12=KM |issn=0028-4793}}</ref>

===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.

Another treatment being investigated is [[Senicapoc]].<ref name="pmid19236269">{{cite journal |author=Ataga KI, Stocker J |title=Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia |journal=Expert Opin Investig Drugs |volume=18 |issue=2 |pages=231–9 |year=2009 |month=February |pmid=19236269 |doi=10.1517/13543780802708011 |url=http://www.informapharmascience.com/doi/abs/10.1517/13543780802708011 |issn=1354-3784	}}</ref>

==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 [[fetus]] or a sample of [[amniotic fluid]]. Since taking a blood sample from a fetus has greater risks, the latter test is usually used. 

After the mutation responsible for this disease was discovered in 1979, the [[U.S. Air Force]] required black 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.<ref>{{cite news |author=Anonymous |title=Air force academy sued over sickle cell policy|url=http://query.nytimes.com/gst/fullpage.html?sec=health&res=9807EFD7163BF937A35752C0A967948260 |work=New York Times |date=4 January 1981 |accessdate=21 December 2008}}</ref>

==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]]. <ref>{{cite journal |author=Herrick, J.B. |title=Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia |journal=Archives of Internal Medicine |volume=6 | pages=517–521 |year=1910 }}</ref>

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 |month=Jan |issn=0098-7484 |url=http://www.nlm.nih.gov/medlineplus/sicklecellanemia.html |format=Free full text}}</ref>

The disease was named "sickle-cell anaemia" by [[Vernon Mason]] in 1922. However, 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, when 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 black 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]], and it was published in their paper "[[Sickle Cell Anemia, a Molecular Disease]]".

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.<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>

==See also==
* [[Hematopoietic ulcer]]
* [[African_admixture_in_Europe#Sickle_cell_trait|African admixture in Europe]]

==References==
{{reflist|2}}

==External links==
* {{DMOZ|Health/Conditions_and_Diseases/Blood_Disorders/Sickle_Cell|Sickle cell}}

{{Hematology}}

[[Category:Blood disorders]]
[[Category:Chronic pain syndromes]]
[[Category:Genetic disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Health in Africa]]

[[ar:فقر الدم المنجلي]]
[[bn:কাস্তে-কোষ ব্যাধি]]
[[bg:Сърповидно-клетъчна анемия]]
[[ca:Anèmia de cèl·lules falciformes]]
[[cs:Srpkovitá anémie]]
[[de:Sichelzellenanämie]]
[[es:Anemia falciforme]]
[[eo:Serpoĉela anemio]]
[[fa:کم‌خونی داسی‌شکل]]
[[fr:Drépanocytose]]
[[gl:Anemia drepanocítica]]
[[ko:겸형 적혈구 빈혈증]]
[[hr:Anemija srpastih stanica]]
[[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]]
[[simple:Sickle-cell disease]]
[[sl:Srpastocelična anemija]]
[[sr:Српаста анемија]]
[[fi:Sirppisoluanemia]]
[[sv:Sicklecellanemi]]
[[zh:鐮刀型紅血球疾病]]