Sickel Cell Desorder

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OMIM 603903 DiseasesDB 12069 MedlinePlus 000527

eMedicinemed/2126oph/490ped/2096emerg/26emerg/406

MeSH C15.378.071.141.150.150

GeneReviews Sickle-cell disease

Sickle-cell disease(SCD), or sickle-cell anemia(or anemia,SCA) or drepanocytosis, is an autosomalrecessivegeneticblood disorderwithoverdominance,characterized byred bloodcellsthat assume an abnormal, rigid,sickleshape. Sicklingdecreases the cells' flexibility and results in a risk of variouscomplications. The sickling occurs because of amutationin thehemoglobingene.Life expectancy is shortened. In 1994, in theUS, the average life expectancy of persons with this condition

was estimated to be 42 years in males and 48 years in females,[1]but today, thanks to better management of the disease, patientscan live into their 50s or beyond.[2]In the UK, the current lifeexpectancy is estimated to be 5360 years of age.[3]

Sickle-cell disease occurs more commonly in people (or theirdescendants) from parts oftropicalandsub-tropicalregionswheremalariais or was common. In areas where malaria iscommon, there is afitnessbenefit in carrying only a singlesickle-cell gene (sickle cell trait). Those with only one of thetwo allelesof the sickle-cell disease, while not totally resistant,are more tolerant to the infection and thus show less severesymptoms when infected.[4]
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03http://en.wikipedia.org/wiki/OMIM


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Sickle-cell anemia is the name of a specific form of sickle-celldisease in which there ishomozygosityfor themutationthatcauses HbS. Sickle-cell anemia is also referred to as "HbSS",

"SS disease", "haemoglobin S" or permutations thereof. Inheterozygouspeople, who have only one sickle gene and onenormal adult haemoglobin gene, it is referred to as "HbAS" or"sickle cell trait". Other, rarer forms of sickle-cell diseaseinclude sickle-haemoglobin Cdisease (HbSC), sickle beta-plus-thalassaemia(HbS/+) and sickle beta-zero-thalassaemia(HbS/0). These other forms of sickle-cell disease arecompoundheterozygousstates in which the person has only one copy of the

mutation that causes HbS and one copy of another abnormalhaemoglobinallele.

The term diseaseis applied, because the inherited abnormalitycauses a pathological condition that can lead to death and severecomplications. Not all inherited variants ofhaemoglobinaredetrimental, a concept known asgenetic polymorphism.

Contents

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1 Signs and symptomso 1.1 Sickle cell crisis

1.1.1 Vaso-occlusive crisis 1.1.2 Splenic sequestration crisis 1.1.3 Aplastic crisis 1.1.4 Haemolytic crisis 1.1.5 Other

o 1.2 Complicationso 1.3 Heterozygotes
http://en.wikipedia.org/wiki/Homozygotehttp://en.wikipedia.org/wiki/Homozygotehttp://en.wikipedia.org/wiki/Homozygotehttp://en.wikipedia.org/wiki/Genetic_mutationhttp://en.wikipedia.org/wiki/Genetic_mutationhttp://en.wikipedia.org/wiki/Genetic_mutationhttp://en.wikipedia.org/wiki/Heterozygoushttp://en.wikipedia.org/wiki/Heterozygoushttp://en.wikipedia.org/wiki/Haemoglobin_Chttp://en.wikipedia.org/wiki/Haemoglobin_Chttp://en.wikipedia.org/wiki/Thalassaemiahttp://en.wikipedia.org/wiki/Thalassaemiahttp://en.wikipedia.org/wiki/Compound_heterozygoushttp://en.wikipedia.org/wiki/Compound_heterozygoushttp://en.wikipedia.org/wiki/Compound_heterozygoushttp://en.wikipedia.org/wiki/Compound_heterozygoushttp://en.wikipedia.org/wiki/Haemoglobinhttp://en.wikipedia.org/wiki/Allelehttp://en.wikipedia.org/wiki/Allelehttp://en.wikipedia.org/wiki/Allelehttp://en.wikipedia.org/wiki/Haemoglobinhttp://en.wikipedia.org/wiki/Haemoglobinhttp://en.wikipedia.org/wiki/Haemoglobinhttp://en.wikipedia.org/wiki/Genetic_polymorphismhttp://en.wikipedia.org/wiki/Genetic_polymorphismhttp://en.wikipedia.org/wiki/Genetic_polymorphismhttp://en.wikipedia.org/wiki/Sickle-cell_diseasehttp://en.wikipedia.org/wiki/Sickle-cell_disease#Signs_and_symptomshttp://en.wikipedia.org/wiki/Sickle-cell_disease#Signs_and_symptomshttp://en.wikipedia.org/wiki/Sickle-cell_disease#Sickle_cell_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Sickle_cell_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Vaso-occlusive_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Vaso-occlusive_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Splenic_sequestration_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Splenic_sequestration_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Aplastic_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Aplastic_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Haemolytic_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Haemolytic_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Otherhttp://en.wikipedia.org/wiki/Sickle-cell_disease#Otherhttp://en.wikipedia.org/wiki/Sickle-cell_disease#Complicationshttp://en.wikipedia.org/wiki/Sickle-cell_disease#Complicationshttp://en.wikipedia.org/wiki/Sickle-cell_disease#Heterozygoteshttp://en.wikipedia.org/wiki/Sickle-cell_disease#Heterozygoteshttp://en.wikipedia.org/wiki/Sickle-cell_disease#Heterozygoteshttp://en.wikipedia.org/wiki/Sickle-cell_disease#Complicationshttp://en.wikipedia.org/wiki/Sickle-cell_disease#Otherhttp://en.wikipedia.org/wiki/Sickle-cell_disease#Haemolytic_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Aplastic_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Splenic_sequestration_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Vaso-occlusive_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Sickle_cell_crisishttp://en.wikipedia.org/wiki/Sickle-cell_disease#Signs_and_symptomshttp://en.wikipedia.org/wiki/Sickle-cell_diseasehttp://en.wikipedia.org/wiki/Genetic_polymorphismhttp://en.wikipedia.org/wiki/Haemoglobinhttp://en.wikipedia.org/wiki/Allelehttp://en.wikipedia.org/wiki/Haemoglobinhttp://en.wikipedia.org/wiki/Compound_heterozygoushttp://en.wikipedia.org/wiki/Compound_heterozygoushttp://en.wikipedia.org/wiki/Thalassaemiahttp://en.wikipedia.org/wiki/Haemoglobin_Chttp://en.wikipedia.org/wiki/Heterozygoushttp://en.wikipedia.org/wiki/Genetic_mutationhttp://en.wikipedia.org/wiki/Homozygote


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Sickle cells in human blood: both normal red blood cells andsickle-shaped cells are present

Sickle-cell disease may lead to various acute and chronic

complications, several of which have a high mortality rate.[5]

[edit] Sickle cell crisis

The term "sickle cell crisis" is used to describe severalindependent acute conditions occurring in patients with sicklecell disease. Sickle cell disease results in anemia and crisis thatcould be of many types including thevaso-occlusive crisis,

aplastic crisis,sequestration crisis,haemolytic crisisand others.Most episodes of sickle cell crises last between five and sevendays.[6]

[edit] Vaso-occlusive crisis

Thevaso-occlusive crisisis caused by sickle-shaped red bloodcells that obstruct capillaries and restrict blood flow to an organ,

resulting inischaemia,pain,necrosisand often organ damage.The frequency, severity, and duration of these crises varyconsiderably. Painful crises are treated with hydration,analgesics, and blood transfusion; pain management requiresopioidadministration at regular intervals until the crisis has
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settled. For milder crises, a subgroup of patients manage onNSAIDs(such asdiclofenacornaproxen). For more severecrises, most patients require inpatient management for

intravenous opioids;patient-controlled analgesia(PCA) devicesare commonly used in this setting. Vaso-occlusive crisisinvolving organs such as the penis or lungs are considered anemergency and treated with red-blood cell transfusions.Diphenhydramineis sometimes effective for the itchingassociated with the opioid use.Incentive spirometry,a techniqueto encourage deep breathing to minimise the development ofatelectasis,is recommended.[7]

[edit] Splenic sequestration crisis

Because of its narrow vessels and function in clearing defectivered blood cells, thespleenis frequently affected.[8]It is usuallyinfarctedbefore the end of childhood in individuals sufferingfrom sickle-cell anemia. Thisautosplenectomyincreases the riskof infection fromencapsulated organisms;[9][10]preventive

antibiotics and vaccinations are recommended for those withsuchasplenia.

Splenic sequestration crises: are acute, painfulenlargements of the spleen. The sinusoids and gates wouldopen at the same time resulting in sudden pooling of theblood into the spleen and circulatory defect leading tosudden hypovolaemia. The abdomen becomes bloated andvery hard. Splenic sequestration crises are considered anemergency. If not treated, patients may die within 12hours due to circulatory failure. Management is supportive,sometimes with blood transfusion. These crises are
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Another recognised type of sickle crisis is theacute chestsyndrome,a condition characterised by fever, chest pain,difficulty breathing, and pulmonary infiltrate on achest X-ray.

Given that pneumonia and sickling in the lung can both producethese symptoms, the patient is treated for both conditions.[16]Itcan be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiateadministration, or surgery.

[edit] Complications

Sickle-cell anemia can lead to various complications, including: Overwhelming post-(auto)splenectomy infection(OPSI),

which is due to functional asplenia, caused by encapsulatedorganisms such asStreptococcus pneumoniaeandHaemophilus influenzae.Dailypenicillinprophylaxis is themost commonly used treatment during childhood, withsome haematologists continuing treatment indefinitely.

Patients benefit today from routine vaccination forH.influenzae, S. pneumoniae, andNeisseria meningitidis. Stroke,which can result from a progressive narrowing of

blood vessels, preventing oxygen from reaching thebrain.Cerebral infarction occurs in children and cerebralhaemorrhage in adults.

Silent strokeis a stroke that causes no immediatesymptoms but is associated with damage to the brain. Silentstroke is probably five times as common as symptomaticstroke. Approximately 1015% of children with sickle celldisease suffer strokes, with silent strokes predominating inthe younger patients.[17][18]
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Cholelithiasis(gallstones) andcholecystitis,which mayresult from excessivebilirubinproduction and precipitationdue to prolongedhaemolysis.

Avascular necrosis (aseptic bone necrosis) of the hip andother major joints, which may occur as a result ofischaemia.[19]

Decreasedimmune reactionsdue tohyposplenism(malfunctioning of the spleen).[20]

Priapismandinfarctionof thepenis.[21] Osteomyelitis(bacterial bone infection); the most common

cause of osteomyelitis in sickle cell disease isSalmonella

(especially the non-typical serotypes Salmonellatyphimurium, Salmonella enteritidis, Salmonellacholeraesuis and Salmonella paratyphi B), followed byStaphylococcus aureusand Gram-negative enteric bacilliperhaps because intravascular sickling of the bowel leads topatchy ischaemic infarction.[22]

Opioidtolerance, which can occur as a normal, physiologic

response to the therapeutic use of opiates. Addiction toopiates occurs no more commonly among individuals withsickle-cell disease than among other individuals treatedwith opiates for other reasons.

Acute papillary necrosisin the kidneys. Leg ulcers.[23] In eyes, background retinopathy, proliferative retinopathy,

vitreous haemorrhages and retinal detachments, resulting inblindness.[24]Regular annual eye checks are recommended.

During pregnancy,intrauterine growth retardation,spontaneousabortion,andpre-eclampsia.
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Chronic pain: Even in the absence of acute vaso-occlusivepain, many patients have chronic pain that is notreported.[25]

Pulmonary hypertension(increased pressure on thepulmonary artery), leading to strain on theright ventricleand a risk ofheart failure;typical symptoms are shortnessof breath, decreased exercise tolerance and episodes ofsyncope.[26]

Chronicrenal failuredue toSickle cell nephropathymanifests itself withhypertension(high blood pressure),proteinuria(protein loss in the urine),haematuria(loss of

red blood cells in urine) and worsened anaemia. If itprogresses to end-stage renal failure, it carries a poorprognosis.[27]

[edit] Heterozygotes

The heterozygous form (sickle cell trait) is almost alwaysasymptomatic, and the only usual significant manifestation is the

renal concentrating defect presenting withisosthenuria.

[edit] Pathophysiology
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Scanning Electron Micrograph showing a mixture of cells, somewith round normal morphology, some with mild sicklingshowing elongation and bending

Sickle-cell anaemia is caused by apoint mutationin the -globinchain ofhaemoglobin,causing the hydrophilic amino acidglutamic acidto be replaced with the hydrophobic amino acidvalineat the sixth position. The -globin gene is found onchromosome 11.[28]The association of twowild-type-globinsubunits with two mutant -globin subunits forms haemoglobinS (HbS). Under low-oxygen conditions (being at high altitude,

for example), the absence of a polar amino acid at position six ofthe -globin chain promotes the non-covalent polymerisation(aggregation) of haemoglobin, which distorts red blood cellsinto a sickle shape and decreases their elasticity.

The loss of red blood cell elasticity is central to thepathophysiology of sickle-cell disease. Normal red blood cellsare quite elastic, which allows the cells to deform to pass

through capillaries. In sickle-cell disease, low-oxygen tensionpromotes red blood cell sickling and repeated episodes ofsickling damage the cell membrane and decrease the cell'selasticity. These cells fail to return to normal shape when normaloxygen tension is restored. As a consequence, these rigid bloodcells are unable to deform as they pass through narrowcapillaries, leading to vessel occlusion andischaemia.

The actual anemia of the illness is caused byhaemolysis,thedestruction of the red cells, because of their misshape. Althoughthebone marrowattempts to compensate by creating new redcells, it does not match the rate of destruction.[29]Healthy red
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blood cells typically live 90120 days, but sickle cells onlysurvive 1020 days.[30]

Normally, humans have Haemoglobin A, which consists of two

alpha and two beta chains, Haemoglobin A2, which consists oftwo alpha and two delta chains and Haemoglobin F, consistingof two alpha and two gamma chains in their bodies. Of these,Haemoglobin A makes up around 96-97% of the normalhaemoglobin in humans.

[edit] Genetics

Sickle-cell gene mutation probably arose spontaneously indifferent geographic areas, as suggested by restrictionendonuclease analysis. These variants are known as Cameroon,Senegal, Benin, Bantu and Saudi-Asian. Their clinicalimportance springs from the fact that some of them areassociated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.[31]

In peopleheterozygousfor HgbS (carriersof sicklinghaemoglobin), the polymerisation problems are minor, becausethe normalalleleis able to produce over 50% of thehaemoglobin. In peoplehomozygousfor HgbS, the presence oflong-chain polymers of HbS distort the shape of the red bloodcell from a smoothdoughnut-like shape to ragged and full ofspikes, making it fragile and susceptible to breaking within

capillaries.Carriers have symptoms only if they are deprived ofoxygen (for example, while climbing a mountain) or whileseverelydehydrated.Under normal circumstances, these painfulcrises occur about 0.8 times per year per patient.[citation needed]Thesickle-cell disease occurs when the seventh amino acid (if the
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initial methionine is counted), glutamic acid, is replaced byvaline to change its structure and function. Valine ishydrophobic, causing the haemoglobin to collapse in on itself

occasionally. The structure is not changed otherwise. Whenenough haemoglobin collapses in on itself the red blood cellsbecome sickle-shaped.

Distribution of the sickle-cell trait shown in pink and purple

Historical distribution ofmalaria(no longer endemic in Europe)

shown in green

Modern distribution of malaria

The gene defect is a knownmutationof a singlenucleotide(see

single-nucleotide polymorphism- SNP) (A to T) of the -globingene, which results inglutamic acidbeing substituted byvalineat position 6. Haemoglobin S with this mutation is referred to asHbS, as opposed to the normal adult HbA. The genetic disorderis due to themutationof a single nucleotide, from a CTC to
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CACcodonon the template strand, which is transcribed into aGUG codon. This is normally a benign mutation, causing noapparent effects on thesecondary,tertiary,orquaternary

structureof haemoglobin in conditions of normaloxygenconcentration. What it does allow for, under conditions of lowoxygenconcentration, is thepolymerizationof the HbS itself.The deoxy form of haemoglobin exposes a hydrophobic patchon the protein between the E and F helices. The hydrophobicresidues of the valine at position 6 of the beta chain inhaemoglobin are able to associate with the hydrophobic patch,causing haemoglobin S molecules to aggregate and form fibrous

precipitates.

Thealleleresponsible for sickle-cell anaemia isautosomalrecessiveand can be found on the short arm of chromosome 11.A person that receives the defective gene from both father andmother develops the disease; a person that receives onedefective and one healthy allele remains healthy, but can pass onthe disease and is known as acarrier.If two parents who arecarriers have a child, there is a 1-in-4 chance of their childdeveloping the disease and a 1-in-2 chance of their child beingjust a carrier. Since thegeneis incompletely recessive, carrierscan produce a few sickled red blood cells, not enough to causesymptoms, but enough to give resistance to malaria. This doesnot confer full immunity to malaria; heterozygotes are still ableto contract malaria, but their symptoms are generally less

severe.[32]Because of this, heterozygotes have a higherfitnessthan either of the homozygotes. This is known asheterozygoteadvantage.
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Due to the adaptive advantage of the heterozygote, the disease isstill prevalent, especially among people with recent ancestry inmalaria-stricken areas, such asAfrica,theMediterranean,India

and theMiddle East.

[33]

Malaria was historically endemic tosouthern Europe, but it was declared eradicated in the mid-20thcentury, with the exception of rare sporadic cases.[34]

The malaria parasite has a complex life cycle and spends part ofit in red blood cells. In a carrier, the presence of the malariaparasite causes the red blood cells with defective haemoglobinto rupture prematurely, making theplasmodiumunable to

reproduce. Further, the polymerization of Hb affects the abilityof the parasite to digest Hb in the first place. Therefore, in areaswhere malaria is a problem, people's chances of survivalactually increase if they carry sickle-cell trait (selection for theheterozygote).

In theUSA,where there is no endemic malaria, the prevalenceof sickle-cell anaemia among blacks is lower (about 0.25%) than

inWest Africa(about 4.0%) and is falling. Without endemicmalaria, the sickle cell mutation is purely disadvantageous andwill tend to be selected out of the affected population. However,the so-called African American community of theUSAisknown to be the result of significant admixture between severalAfrican and non-African ethnic groups, and also represents thedescendants of survivors of the slavery and the slave trade.

Thus, a lower degree of endogamy and, particularly, abnormallyhigh health-selective pressure through slavery may be the mostplausible explanations for the lower prevalence of sickle-cellanaemia (and, possibly, other genetic diseases) among Afro-Americans compared to Sub-Saharan African people. Another
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factor limiting the spread of sickle-cell genes in North Americais the absence of cultural proclivities to polygamy, which allowsaffected males to continue to seek unaffected children with

multiple partners.

[35]

Sickle-cell disease is inherited in the autosomal recessivepattern.

[edit] Inheritance

Sickle-cell conditions are inherited from parents in much thesame way as blood type, hair color and texture, eye colour, andother physical traits. The types of haemoglobin a person makesin the red blood cells depend on what haemoglobin genes areinherited from his parents. If one parent has sickle-cell anaemia(SS) and the other has sickle-cell trait then there is a 50% chanceof a child's having sickle-cell disease and a 50% chance of a

child's having sickle-cell trait. When both parents have sickle-cell trait a child has a 25% chance of sickle-cell disease, asshown in the diagram.

[edit] Diagnosis
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thefetusor a sample ofamniotic fluid.Since taking a bloodsample from a fetus has greater risks, the latter test is usuallyused.

After the mutation responsible for this disease was discovered in1979, theU.S. Air Forcerequired black applicants to test for themutation. It dismissed 143 applicants because they were carriers,even though none of them had the condition. It eventuallywithdrew the requirement, but only after a trainee filed alawsuit.[38]

[edit] Management[edit] Folic acid and penicillin

Children born with sickle-cell disease will undergo closeobservation by the pediatrician and will require management bya haematologist to assure they remain healthy. These patientswill take a 1 mg dose offolic aciddaily for life. From birth to

five years of age, they will also have to take penicillin daily dueto the immature immune system that makes them more prone toearly childhood illnesses.

[edit] Malaria chemoprophylaxis

The protective effect of sickle cell trait does not apply to peoplewith sickle cell disease; in fact, they are uniquely vulnerable tomalaria, since the most common cause of painful crises inmalarial countries is infection with malaria. It has therefore beenrecommended that people with sickle cell disease living inmalarial countries should receive anti-malarialchemoprophylaxis for life.[39]
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[edit] Vaso-occlusive crisis

Most people with sickle-cell disease have intensely painfulepisodes called vaso-occlusive crises. The frequency, severity,

and duration of these crises, however, vary tremendously.Painful crises are treated symptomatically withanalgesics;painmanagement requiresopioidadministration at regular intervalsuntil the crisis has settled. For milder crises, a subgroup ofpatients manage onNSAIDs(such asdiclofenacornaproxen).For more severe crises, most patients require inpatientmanagement for intravenous opioids;patient-controlled

analgesia(PCA) devices are commonly used in this setting.Diphenhydramineis also an effective agent that is frequentlyprescribed by doctors in order to help control any itchingassociated with the use of opioids.

[edit] Acute chest crisis

Management is similar to vaso-occlusive crisis, with the

addition of antibiotics (usually a quinolone or macrolide, sincewall-deficient ["atypical"] bacteria are thought to contribute tothe syndrome),[40]oxygen supplementation forhypoxia,andclose observation. Should the pulmonary infiltrate worsen or theoxygen requirements increase, simpleblood transfusionorexchange transfusionis indicated. The latter involves theexchange of a significant portion of the patients red cell mass fornormal red cells, which decreases the percent of haemoglobin Sin the patient's blood.

[edit] Hydroxyurea
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The first approved drug for the causative treatment of sickle-cellanaemia,hydroxyurea,was shown to decrease the number andseverity of attacks in a study in 1995 (Charache et al.)[41]and

shown to possibly increase survival time in a study in 2003(Steinberg et al.).[42]This is achieved, in part, by reactivatingfetal haemoglobinproduction in place of the haemoglobin S thatcauses sickle-cell anaemia. Hydroxyurea had previously beenused as achemotherapyagent, and there is some concern thatlong-term use may be harmful, but this risk has been shown tobe either absent or very small and it is likely that the benefitsoutweigh the risks.[43]

[edit] Transfusion therapy

Blood transfusionsare often used in the management of sicklecell disease in acute cases and to prevent complications bydecreasing the number of red blood cells (RBC) that can sickleby adding normal red blood cells.[44]In children prophylacticchronic red blood cell (RBC)transfusion therapyhas been

shown to be efficacious to a certain extent in reducing the risk offirst stroke or silent stroke whentranscranial Doppler(TCD)ultrasonographyshows abnormal increased cerebral blood flowvelocities. In those who have sustained a prior stoke event it alsoreduces the risk of recurrent stroke and additional silentstrokes.[45][46]

[edit] Bone marrow transplants

Bone marrow transplantshave proven to be effective inchildren.[47]

[edit] Epidemiology
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The highest frequency of sickle cell disease is found in tropicalregions, particularly sub-Saharan Africa, India and the Middle-East.[48]Migration of substantial populations from these high

prevalence areas to low prevalence countries in Europe hasdramatically increased in recent decades and in some Europeancountries sickle cell disease has now overtaken more familiargenetic conditions such ashaemophiliaandcystic fibrosis.[49]

[edit] Africa

Three quarters of sickle-cell cases occur in Africa. A recent

WHOreport estimated that around 2% of newborns in Nigeriawere affected by sickle cell anaemia, giving a total of 150,000affected children born every year in Nigeria alone. The carrierfrequency ranges between 10% and 40% across equatorialAfrica, decreasing to 12% on the north African coast and


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In the United Kingdom, 1 baby in every 2,000 is born with thiscondition.[3]

[edit] Middle East

In Saudi Arabia about 4.2% of the population carry the sickle-cell trait and 0.26% have sickle cell disease. The highestprevalence is in the Eastern province where approximately 17%of the population carry the gene and 1.2% have sickle celldisease.[61]In 2005 in Saudi Arabia a mandatory pre-marital testincluding HB electrophoresis was launched and aimed to

decrease the incidence of SCD andthalasemia.

[62]

[edit] India

Sickle cell disease is prevalent in many parts of India, where theprevalence has ranged from 9.4 to 22.2% in endemic areas.[63]

[edit] History

This collection of clinical findings was unknown until theexplanation of the sickle cells in 1910 by the Chicagocardiologist and professor of medicineJames B. Herrick(18611954), whose internErnest Edward Irons(18771959) found"peculiar elongated and sickle-shaped" cells in the blood ofWalter Clement Noel, a 20-year-old first-year dental studentfrom Grenada, after Noel was admitted to the ChicagoPresbyterian Hospital in December 1904 suffering fromanaemia.[64]

Noel was readmitted several times over the next three years for"muscular rheumatism" and "bilious attacks". Noel completedhis studies and returned to the capital of Grenada (St. George's)
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to practicedentistry.He died ofpneumoniain 1916 and isburied in the Catholic cemetery atSauteursin the north ofGrenada.[65]Herrick's published account included illustrations,

but the earliest available slide showing sickle cells is that of a1918 autopsy from a soldier with sickle trait, initially reviewedonly 92 years later.[66]

The disease was named "sickle-cell anemia" byVerne Masonin1922, then a medical resident atJohns Hopkins Hospital.[67]However, some elements of the disease had been recognizedearlier: A paper in the Southern Journal of Medical

Pharmacologyin 1846 described the absence of a spleen in theautopsyof a runaway slave. The African medical literaturereported this condition in the 1870s, when it was known locallyas ogbanjes("children who come and go") because of the veryhigh infant mortality rate caused by this condition. A history ofthe condition tracked reports back to 1670 in one Ghanaianfamily.[68]

Linus Paulingand colleagues were the first, in 1949, todemonstrate that sickle-cell disease occurs as a result of anabnormality in the haemoglobin molecule. This was the firsttime a genetic disease was linked to a mutation of a specificprotein, a milestone in thehistory of molecular biology,and itwas published in their paper "Sickle Cell Anemia, a MolecularDisease".
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