Sickle Cell Crisis Overview Sickle cell diseaseis the most common of the hereditary blood disorders.It occursalmost exclusively among black Americans and black Africans. Sickle cell disease in black Americans occurs in 3 of every 1,000 (or about 1 in 375) live births. Estimates indicate that the severe form of sickle cell disease affectsmore than 50,000 black Americans. The first account of what was then called sickle cell anemiain the medical literature was in 1910. James B. Herrick, a Chicago physician, described the symptoms of a 20-year-old black male student from the West Indies. The man had reported "shortness of breath, palpitations, and episodes oficterus[yellow eyes]. He had an anemia." Dr. Herrick described the patient's blood smear as showing "thin, sickle-shaped and crescent-shaped red cells." Red blood cellsdeliveroxygento working or active tissues. In thelungs,hemoglobin(themoleculein thered blood cell) takes on oxygen and, at the same time, releases carbon dioxide. This process is calledoxygenation.At the tissue level, this activity is reversed. The same hemoglobin molecule releases oxygen and takes on carbon dioxide. This process is calleddeoxygenation. In sickle cell disease, certain red blood cells become crescent-shaped (the sickle cell Dr. Herrick described). Theseabnormalred blood cells, carrying an abnormal hemoglobin known as hemoglobin S, are fragile. A person who hassickle cell disease can become more likely to get infections because the damaged cells eventually clog thespleen. A severe attack, known as sickle cell crisis, can cause painbecause blood vessels can become blocked or the defective red blood cells can damage organs in the body. The words homozygous, heterozygous, and hemizygous are used to describe the genotypeof a diploid organism at a singlelocuson the DNA.Homozygous describes a genotype consisting of two identical alleles at a given locus, heterozygous describes a genotype consisting of two different alleles at a locus, hemizygous describes a genotype consisting of only a single copy of a particular gene in an otherwise diploid organism, and nullizygousrefers to an otherwise diploid organism in which both copies of the gene are missing. Sickle Cell Crisis Causes Sickle cell disease results frommutation, or change, of certain types of hemoglobin chains in red blood cells (the beta hemoglobin chains). The changes in the building of normal hemoglobin result in the abnormal hemoglobin of sickle cell disease. These mutated molecules do not have the smooth motion needed for oxygenation and deoxygenation. When the oxygen concentration in the blood is reduced, the red blood cell assumes the characteristic sickle shape. This causes the red blood cell to be stiff and rigid, and stops the smooth passage of the red blood cells through the narrow blood vessels. It does not take much imagination to see sharp-end "sickled" red cells stacking up in narrow blood vessels known ascapillaries. When this happens, red blood cells are not able to carry oxygen to tissues, and tissue cell injuryor death occurs. Someone with sickle cell disease would be experiencing pain with this process-the sickle cell crisis. Sickle Cell Crisis Symptoms The sites most often affected by the blocking or stacking action of sickled cells are found in the lungs, liver,bone, muscles, brain, spleen,penis, eyes, and kidneys.
Sickle cell disease is the most common of the hereditary blood disorders.It occursalmost exclusively amongblack Americans and black Africans.
Sickle cell disease in black Americans occurs in 3 of every 1,000 (or about 1 in 375) live births. Estimatesindicate that the severe form of sickle cell disease affectsmore than 50,000 black Americans.
The first account of what was then called sickle cell anemia in the medical literature was in 1910. James B.Herrick, a Chicago physician, described the symptoms of a 20-year-old black male student from the WestIndies. The man had reported "shortness of breath, palpitations, and episodes of icterus [yellow eyes]. He had ananemia." Dr. Herrick described the patient's blood smear as showing "thin, sickle-shaped and crescent-shapedred cells."
Red blood cells deliver oxygen to working or active tissues. In the lungs, hemoglobin (the molecule in the redblood cell) takes on oxygen and, at the same time, releases carbon dioxide. This process is called oxygenation. At the tissue level, this activity is reversed. The same hemoglobin molecule releases oxygen and takes oncarbon dioxide. This process is calleddeoxygenation.
In sickle cell disease, certain red blood cells become crescent-shaped (the sickle cell Dr. Herrick described).These abnormal red blood cells, carrying an abnormal hemoglobin known as hemoglobin S, are fragile. Aperson who hassickle cell disease can become more likely to get infections because the damaged cellseventually clog the spleen. A severe attack, known as sickle cell crisis, can cause pain because blood vesselscan become blocked or the defective red blood cells can damage organs in the body.
The words homozygous, heterozygous, and hemizygous are used to describe the genotype of a diploid organismat a single locus on the DNA. Homozygous describes a genotype consisting of two identical alleles at a givenlocus, heterozygous describes a genotype consisting of two different alleles at a locus, hemizygous describes agenotype consisting of only a single copy of a particular gene in an otherwise diploid organism, and nullizygous
refers to an otherwise diploid organism in which both copies of the gene are missing.
Sickle Cell Crisis Causes
Sickle cell disease results from mutation, or change, of certain types of hemoglobin chains in red blood cells(the beta hemoglobin chains).
The changes in the building of normal hemoglobin result in the abnormal hemoglobin of sickle cell disease.These mutated molecules do not have the smooth motion needed for oxygenation and deoxygenation. When theoxygen concentration in the blood is reduced, the red blood cell assumes the characteristic sickle shape. Thiscauses the red blood cell to be stiff and rigid, and stops the smooth passage of the red blood cells through thenarrow blood vessels.
It does not take much imagination to see sharp-end "sickled" red cells stacking up in narrow blood vesselsknown as capillaries. When this happens, red blood cells are not able to carry oxygen to tissues, and tissue cellinjury or death occurs. Someone with sickle cell disease would be experiencing pain with this process-the sicklecell crisis.
Sickle Cell Crisis Symptoms
The sites most often affected by the blocking or stacking action of sickled cells are found in the lungs, liver, bone, muscles, brain, spleen, penis, eyes, and kidneys.
The immune system of a person with sickled cellsdramatically weakens. People with sickle cells arehighlysusceptible to infections from certain forms of bacteria. Some of the most common infections are from flu viruses, pneumonia, and salmonella (a type of bacteria).
Severe pain is the most common of sickle cell disease emergencies (acute sickle cellcrises). A personmay notknow what brought on the pain, but one or more of the following situations may have contributed to the start of the painful sickle crisis:
Dehydration
Infection
Fever
Hypoxia (decrease in oxygen to body tissue)
Bleeding
Cold exposure
Drug and alcohol use
Pregnancy and stress
Fourpatterns of an acute sickle cell crisis are now recognizable. They are based on the part of the body wherethe crisis occurs.
Bone crisis: An acute or sudden pain in a bone can occur, usually in an arm or leg. The area may betender. Common bones involved include the large bones in the arm or leg: the humerus, tibia, and femurThe same bone may be affected repeatedly in future episodes of bone crisis.
Acute chest syndrome: Sudden acute chest pain with coughing up of blood can occur. Low-grade feverscan be present. The person is usually short of breath. If a cough is present, it often isnonproductive.Acute chest syndrome is common in a young person with sickle cell disease. Chronic (long-term) sickle cell lung disease develops with time because the acute and subacute lung crisis leadsto scarred lungs and other problems.
Abdominal crisis: The pain associated with the abdominal crisis of sickle cell disease is constant andsudden. It becomes unrelenting. The pain may or maynot be localized to any one area of the abdomen. Nausea, vomiting, and diarrhea may or may not occur.
Joint crisis: Acute and painful joint crisis may develop without a significant traumatic history. Its focus
iseither ina single jointor in multiple joints. Often the connecting bony parts of the joint are painful.Range of motion is often restricted because of the pain.
Many other organ systems are often injured orimpaired.
Central nervous system: Two-thirds of all strokes in people with sickle cell disease occur in children, atan average age of8 years. About 10% of people with sickle cell disease have strokes or other brainbleeding when younger than 8-10 years. As the population ages, the incidence of these events alsoincreases. Repeat strokes occur in two-thirds of all survivors within 3 years of the first stroke. Bloodclots affect the large vessels in the brain. Bleeding may occur in the small vessels damaged by sickle celldisease.
Eyes: The effectofsickle cell disease on the eyes comes from the increased viscosity, or "sludging," of blood and the narrowness of the eye's blood vessels. Retinopathy (disease of the retina in the eye) iscommon and causes problems with vision. Retinal detachment is frequent. Hyphemas, bleeding in theeye, occur at the same rate as the general population, but complications are more common because of the increased sickling effect that the waterlikefluid in the eye promotes.
Kidneys: Some amount of kidney damage occurs in nearly every person with sickle cell disease.
Genitals: Priapism (a constant erection of the penis) is common. It affects about 40% of all men withsickle cell disease. Severe episodes are a frequent cause of impotency.
Infections: People with sickle cell disease have weakened immune systems and are at increased risk fordeveloping infection, especially in the lungs, kidneys, bones, and central nervous system.
Blood problems: People with sickle cell disease can develop anemia-a reduction in the number of redblood cells. Symptoms of anemia are shortness of breath (oxygen is not getting to tissues),lightheadedness, and fatigue.
When to Seek Medical Care
If certain conditions develop in a person withsickle cell disease, the personmust contact a physician. If thephysicianis not quickly available or cannot see the person right away, the person with sickle cell diseasemaychoose to go to a hospital's emergency department. Contact the physicianin the followingcases:
Many people with sickle-cell disease have pain with enough frequency that they need to take painmedications at home. If the pain is unrelieved by the medication, or the pain is significantly differentfromprevious episodes, contact the health care provider.
Ifexperiencing nausea, vomiting, and diarrhea;losing a lot of fluid; and having inabilityto drink and keepit down, the person with sickle cell disease isin danger of becoming dehydrated. This is a seriousconcern with sickle cell disease. The physicianor the hospital may provideIV fluids to replace the lostfluids.
It is important to control infection. If it appears that a person with sickle cell disease isgetting aninfection, even ifusing antibiotics to prevent infection,contact the physician immediately.
A sickle cell crisis can often be managed efficiently and quickly in a hospital's emergency department withfluids and pain medicines. A person with sickle cell disease shouldnot delay going to the hospital. Delay canonly make the condition worse and might requirehospitalizationfor treatment.
Go to a hospital's emergency department if these conditions develop:
Uncontrollable pain even with the use of narcotics
Continued loss of fluid leading to dehydration (ifvomiting)
The health care providerwill take the complete medical history of a person with sickle cell disease. Thishistoryshould includewhetherany infections are present. The health care provider will ask about other problems that arecommon starters of sickle cell crisis. These problems would be a lack of oxygen in the tissue, bleeding,dehydration, alcohol and drug use, pregnancy, and other concerns.
During a physical exam, the physician will check the nervous system, lungs, bones, eyes, and abdomen,in particular.
The physician will perform blood and urine tests. If indicated, the physician may have a CT scan of the
head taken and perform a spinal tap to check for problems in the spinal fluid and brain.
If the physician suspects sickle cell disease in an adult, or more commonly a child not previously diagnosedwith this disease, attention will first be paid to getting a family history of sickle cell disease. The physician thenperforms a blood test to diagnose the disease.
Sickle Cell Crisis Treatment
Self-Care at Home
Even tiny changes in the red blood cells can begin a cascade of symptoms leading to a sickle cell crisis.Therefore, home care, even when a person iscareful about drinking plenty of fluids and avoiding infection, isdifficult. The best home care is understanding the illness and knowing when and where to seek immediatemedical care.
Medications
Sickle cell pain crisis
o Pain medications, often narcotics, will be given.o o IV fluids are an important part of therapy.
Infection: If the physician diagnoses or suspects a bacterial infection, antibiotics are prescribed. Anemia: If there is a significant decrease in the red blood cell count, a red blood cell transfusion may be
needed.
Other Therapy
Chronic therapy: New developments in regularly scheduled transfusion therapy have shown promise indecreasing the following:
o Symptoms of acute chest syndromeo o Incidence of strokeo o Severity of pain crises
Bone marrow transplantation holds promise for a very small percentage of people with sickle cell
Considering the many body systems involved and the likelihood that sickle cell crisis will occur time and timeagain, strong consideration should be given to follow-up with a hematologist (a physician with a specialty intreating blood disorders).
Most uncomplicated cases of sickle cell crisis can be treated in community emergency departments. People withthis condition can be safely sent home when their pain is under control and their dehydration is eliminated. A
short observational period in the emergency department helps to prevent acute relapse and admission for painand rehydration.
Outpatient treatmentcenterson the control of infection, reduction of pain, and prevention of dehydration. Theuse of narcotics is often necessary and should not be limited for fear of turning someone with sickle cell diseaseinto a drug addict.
[edit] Homozygous
A cell is said to be homozygous for a particular gene when identical alleles of the gene are present on bothhomologous chromosomes.[2] The cell or organism in question is called a homozygote. True breeding organismsare always homozygous for the traits that are to be held constant.
An individual that is homozygous dominant for a particular trait carries two copies of the allele that codes forthe dominant trait. This allele, often called the "dominant allele", is normally represented by a capital letter(such as "P" for the dominant allele producing purple flowers in pea plants). When an organism is homozygousdominant for a particular trait, the genotype is represented by a doubling of the symbol for that trait, such as"PP".
An individual that is homozygous recessive for a particular trait carries two copies of the allele that codes for the
recessive trait. This allele, often called the "recessive allele", is usually represented by the lowercase form of theletter used for the corresponding dominant trait (such as, with reference to the example above, "p" for therecessive allele producing white flowers in pea plants). The genotype of an organism that is homozygousrecessive for a particular trait is represented by a doubling of the appropriate letter, such as "pp".
[edit] Heterozygous
A diploid organism is heterozygous at a gene locus when its cells contain two different alleles of a gene.[3] Heterozygous genotypes are represented by a capital letter (representing the dominant allele) and a lowercaseletter (representing the recessive allele), such as "Rr" or "Ss". The capital letter is usually written first.
If the trait in question is determined by simple (complete) dominance, a heterozygote will express only the traitcoded by the dominant allele and the trait coded by the recessive allele will not be present. In more complexdominance schemes the results of heterozygosity can be more complex.
[edit] Hemizygous
A chromosome in a diploid organism is hemizygous when only one copy is present.[2] The cell or organism iscalled a hemizygote. Hemizygosity is observed when one copy of a gene is deleted, or in the heterogametic sexwhen a gene is located on a sex chromosome. For organisms in which the male is heterogametic, such ashumans, almost all X-linked genes are hemizygous in males with normal chromosomes because they have only
one X chromosome and few of the same genes are on the Y chromosome. In a more extreme example, malehoneybees (known as drones) are completely hemizygous organisms. They develop from unfertilized eggs andtheir entire genome is haploid, unlike female honeybees, which are diploid. Transgenic mice generated throughexogenous DNA microinjection of an embryo's pronucleus are also hemizygous, and can later be bred tohomozygosity to reduce the need to confirm genotype of each litter. [clarification needed ]
[edit] Nullizygous
A nullizygous organism carries two mutant alleles for the same gene. The mutant alleles are both complete loss-of-function or 'null' alleles, so homozygous null and nullizygous are synonymous.[2] The mutant cell ororganism is called a nullizygote.
[edit ] Autozygous and allozygous
Zygosity may also refer to the origin(s) of the alleles in a genotype. When the two alleles at a locus originatefrom a common ancestor by way of nonrandom mating (inbreeding), the genotype is said to be autozygous. Thisis also known as being "identical by descent", or IBD. When the two alleles come (at least to the extent that thedescent can be traced) from completely different sources, as is the case in most normal, random mating, thegenotype is called allozygous. This is known as being "identical by state", or IBS.
Because the alleles of autozygous genotypes come from the same source, they are always homozygous, butallozygous genotypes may be homozygous too. All heterozygous genotypes are, by definition, allozygousbecause they contain two completely different alleles. Hemizygous and nullizygous genotypes do not containenough alleles to allow for comparison of sources, so this classification is irrelevant for them.
Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortalityrate.
[edit] Sickle cell crisis
The term "sickle cell crisis" is used to describe several independent acute conditions occurring in patients withsickle cell disease. Sickle cell disease results in anaemia and crisis that could be of many types including thevaso-occlusive crisis, aplastic crisis, sequestration crisis, haemolytic crisis and others. Most episodes of sicklecell crises last between five and seven days.[6]
[ edit ] Vaso-occlusive crisis
The vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict bloodflow to an organ, resulting in ischaemia, pain, necrosis and often organ damage. The frequency, severity, andduration of these crises vary considerably. Painful crises are treated with hydration, analgesics, and blood
transfusion; pain management requires opioid administration at regular intervals until the crisis has settled. Formilder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severecrises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA)devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis or lungs areconsidered an emergency and treated with red-blood cell transfusions. Diphenhydramine is sometimes effectivefor the itching associated with the opioid use. Incentive spirometry, a technique to encourage deep breathing tominimise the development of atelectasis, is recommended.[citation needed ]
Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequentlyaffected[citation needed ]. It is usually infarcted before the end of childhood in individuals suffering from sickle-cellanaemia. This autosplenectomy increases the risk of infection from encapsulated organisms;[7][8] preventiveantibiotics and vaccinations are recommended for those with such asplenia.
Splenic sequestration crises: are acute, painful enlargements of the spleen. The sinusoids and gates would open
at the same time resulting in sudden pooling of the blood into the spleen and circulatory defect leading tosudden hypovolaemia. The abdomen becomes bloated and very hard. Splenic sequestration crises is considered
an emergency. If not treated, patients may die within 1 –2 hours due to circulatory failure. Management is
supportive, sometimes with blood transfusion. These crises are transient, they continue for 3 –4 hours and may
last for one day.
[ edit ] Aplastic crisis
Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pallor, tachycardia, andfatigue. This crisis is triggered by parvovirus B19, which directly affects erythropoiesis (production of redblood cells) by invading the red cell precursors and multiplying in them and destroying them. Parvovirus
infection nearly completely prevents red blood cell production for two to three days. In normal individuals, thisis of little consequence, but the shortened red cell life of sickle-cell patients results in an abrupt, life-threateningsituation. Reticulocyte counts drop dramatically during the disease (causing reticulocytopenia), and the rapidturnover of red cells leads to the drop in haemoglobin. This crisis takes 4 days to one week to disappear. Mostpatients can be managed supportively; some need blood transfusion.
[ edit ] Haemolytic crisis
Haemolytic crises are acute accelerated drops in haemoglobin level. The red blood cells break down at a fasterrate. This is particularly common in patients with co-existent G6PD deficiency. Management is supportive,sometimes with blood transfusions.
[ edit ] Other
One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occurin children with sickle trait.[9] The crisis can last up to a month.[10] Another recognised type of sickle crisis is theacute chest syndrome, a condition characterised by fever, chest pain, difficulty breathing, and pulmonaryinfiltrate on a chest X-ray. Given that pneumonia and sickling in the lung can both produce these symptoms, thepatient is treated for both conditions.[citation needed ] It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.
[edit] Complications
Sickle-cell anaemia can lead to various complications, including:
Overwhelming post-(auto)splenectomy infection (OPSI), which 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.
Stroke, which can result from a progressive narrowing of blood vessels, preventing oxygen from reaching the
brain. Cerebral infarction occurs in children and cerebral haemorrhage in adults.
Silent stroke is a stroke that causes no immediate symptoms but is associated with damage to the brain. Silent
stroke is probably five times as common as symptomatic stroke. Approximately 10 –15% of children with sickle
cell disease suffer strokes, with silent strokes predominating in the younger patients.[11][12]
Cholelithiasis (gallstones) and cholecystitis, which may result from excessive bilirubin production and
precipitation due to prolonged haemolysis.
Avascular necrosis (aseptic bone necrosis) of the hip and other major joints, which may occur as a result of
ischaemia.[13]
Decreased immune reactions due to hyposplenism (malfunctioning of the spleen).[14]
Priapism and infarction of the penis.[15]
Osteomyelitis (bacterial bone infection); the most common cause of osteomyelitis in sickle cell disease is
Salmonella (especially the non-typical serotypes Salmonella typhimurium, Salmonella enteritidis, Salmonella
choleraesuis and Salmonella paratyphi B), followed by Staphylococcus aureus and Gram-negative enteric bacilli
perhaps because intravascular sickling of the bowel leads to patchy ischaemic infarction.[16]
Opioid tolerance, which 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.
Acute papillary necrosis in the kidneys.
Leg ulcers.[17]
In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages and retinal detachments,
resulting in blindness.[18]
Regular annual eye checks are recommended.
During pregnancy, intrauterine growth retardation, spontaneous abortion, and pre-eclampsia.
Chronic pain: Even in the absence of acute vaso-occlusive pain, many patients have chronic pain that is not
reported.[19]
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.[20]
Chronic renal failure due to Sickle cell nephropathy—manifests itself with hypertension (high blood pressure),
proteinuria (protein loss in the urine), haematuria (loss of red blood cells in urine) and worsened anaemia. If it
progresses to end-stage renal failure, it carries a poor prognosis.[21]
[edit] Heterozygotes
The heterozygous form (sickle cell trait) is almost always asymptomatic, and the only usual significantmanifestation is the renal concentrating defect presenting with isosthenuria.
[edit ] Pathophysiology
Sickle-cell anaemia is caused by a point mutation in the β-globin chain of haemoglobin, causing the hydrophilicamino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position. The β-globin gene is found on chromosome 11, (Robbin's Pathology). The association of two wild-type α-globinsubunits with two mutant β-globin subunits forms haemoglobin S (HbS). Under low-oxygen conditions (beingat high altitude, for example), the absence of a polar amino acid at position six of the β-globin chain promotesthe non-covalent polymerisation (aggregation) of haemoglobin, which distorts red blood cells into a sickleshape and decreases their elasticity.
The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease. Normal red bloodcells 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 membraneand decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension isrestored. 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 anaemia of the illness is caused by haemolysis, 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 doesnot match the rate of destruction.[22] Healthy red blood cells typically live 90 – 120 days, but sickle cells onlysurvive 10 – 20 days.[23]
Normally, humans have Haemoglobin A, which consists of two alpha and two beta chains, Haemoglobin A2,which consists of two alpha and two delta chains and Haemoglobin F, consisting of two alpha and two gammachains in their bodies. Of these, Haemoglobin A makes up around 96-97% of the normal haemoglobin in
humans.
[edit ] Genetics
Sickle-cell gene mutation probably arose spontaneously in different geographic areas, as suggested byrestriction 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.[24]
In people heterozygous for HgbS (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, thepresence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth doughnut-likeshape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers havesymptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severelydehydrated. Under normal circumstances, these painful crises occur about 0.8 times per year per patient. [citation
needed ] The sickle-cell disease occurs when the seventh amino acid (if the initial methionine is counted), glutamicacid, is replaced by valine to change its structure and function. Valine is hydrophobic, causing the haemoglobinto collapse in on itself occasionally. The structure is not changed otherwise. When enough haemoglobincollapses in on itself the red blood cells become sickle-shaped.
Distribution of the sickle-cell trait shown in pink and purple
Historical distribution of malaria (no longer endemic in Europe) shown in green
The gene defect is a known mutation of a single nucleotide (see single-nucleotide polymorphism - SNP) (A toT) of the β-globin gene, which results in glutamic acid being substituted by valine at position 6. Haemoglobin Swith this mutation is referred to as HbS, as opposed to the normal adult HbA. The genetic disorder is due to themutation of a single nucleotide, from a GAG to GTG codon mutation, becoming a GUG codon by transcription.This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternarystructure of haemoglobin in conditions of normal oxygen concentration. What it does allow for, underconditions 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 hydrophobicresidues of the valine at position 6 of the beta chain in haemoglobin are able to associate with the hydrophobicpatch, 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 that receives the defective gene from both father and mother develops the disease; aperson that receives one defective and one healthy allele remains healthy, but can pass on the disease and isknown as a carrier. If two parents who are carriers have a child, there is a 1-in-4 chance of their childdeveloping the disease and a 1-in-2 chance of their child's being just a carrier. Since the gene is incompletelyrecessive, carriers can produce a few sickled red blood cells, not enough to cause symptoms, but enough to giveresistance to malaria. Because of this, heterozygotes have a higher fitness than either of the homozygotes. Thisis known as heterozygote advantage.
Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people withrecent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India and the Middle East.[25] Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century,with the exception of rare sporadic cases.[26]
The malaria parasite has a complex life cycle and spends part of it in red blood cells. In a carrier, the presenceof the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, makingthe plasmodium unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite todigest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actuallyincrease 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 among blacks is lower(about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle cellmutation is purely disadvantageous and will tend to be selected out of the affected population. However, the so-called African American community of the USA is known to be the result of significant admixture betweenseveral African and non-African ethnic groups, and also represents the descendants of survivors of the slaveryand the slave trade. Thus, a lower degree of endogamy and, particularly, abnormally high health-selectivepressure through slavery may be the most plausible explanations for the lower prevalence of sickle-cell anaemia(and, possibly, other genetic diseases) among Afro-Americans compared to Sub-Saharan African people.Another factor limiting the spread of sickle-cell genes in North America is the absence of cultural proclivities topolygamy, which allows affected males to continue to seek unaffected children with multiple partners.[27]
Sickle-cell disease is inherited in the autosomal recessive pattern.
[edit] Inheritance
Sickle-cell conditions are inherited from parents in much the same way as blood type, hair color and texture,eye colour, and other physical traits. The types of haemoglobin a person makes in the red blood cells depend onwhat haemoglobin genes are inherited from his parents. If one parent has sickle-cell anaemia (SS) and the otherhas 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 (1of 4) of sickle-cell disease (SS), as shown in the diagram.
[edit ] Epidemiology
The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, India
and the Middle-East.[28]
Migration of substantial populations from these high prevalence areas to lowprevalence countries in Europe has dramatically increased in recent decades and in some European countriessickle cell disease has now overtaken more familiar genetic conditions such as haemophilia and cysticfibrosis.[29]
[edit] Africa
Three quarters of sickle-cell cases occur in Africa. A recent WHO report estimated that around 2% of newbornsin Nigeria were affected by sickle cell anaemia, giving a total of 150,000 affected children born every year inNigeria alone. The carrier frequency ranges between 10% and 40% across equatorial Africa, decreasing to 1 –
2% on the north African coast and <1% in South Africa.[30]
[edit] Europe
[ edit ] France
In Europe, the highest prevalence of the disease has been observed in France. As a result of population growthin African-Caribbean regions of overseas France, and now immigration essentially from North and sub-SaharanAfrica to mainland France, sickle cell disease has become a major health problem in France.[31] SCD hasbecome the most common genetic disease in this country, with an overall birth prevalence of 1/2,415 inmainland France, ahead of phenylketonuria (1/10,862), congenital hypothyroidism (1/3,132), congenital adrenal
hyperplasia (1/19,008) and cystic fibrosis (1/5,014) for the same reference period. In 2007, 28.45% of allnewborns in mainland France had at least one parent originated from a region defined "at risk" (mainly Africaand Overseas departments and territories of France) and were screened for SCD. The Paris metropolitan district(Île-de-France) is the region that accounts for the largest number of people at presumably higher risk of SCD.Indeed, nearly 56% of all newborns in this area in 2007 had at least one parent originated from a region definedas "at-risk" and were screened for SCD. The second largest number of at-risk is in Provence-Alpes-Côte d'Azur at nearly 42% and the lowest number is in Brittany at 4.40%.[32]
[ edit ] United Kingdom
In United Kingdom, more than 200 babies are born annually with SCD.
[edit] Middle East
About 6,000 children are born annually with SCD, at least 50% of these in Saudi Arabia, especially in Qatif City.
[edit] India
Sickle cell disease is prevalent in many parts of India, where the prevalence has ranged from 9.4 to 22.2% inendemic areas.[33]
[edit ] Diagnosis
In HbSS, the 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 (target cells and Howell-Jolly bodies).
Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. Thepresence 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, whereasnormal Hb gives a clear solution.
Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis onwhich the various types of haemoglobin move at varying speeds. Sickle-cell haemoglobin (HgbS) andhaemoglobin C with sickling (HgbSC) — the two most common forms — can be identified from there. Thediagnosis can be confirmed with high-performance liquid chromatography (HPLC). Genetic testing is rarelyperformed, as other investigations are highly specific for HbS and HbC.[34]
An acute sickle-cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an occult urinarytract infection, and chest X-ray to look for occult pneumonia should be routinely performed.[35]
People who are known carriers of the disease often undergo genetic counseling before they have a child. A testto see if an unborn child has the disease takes either a blood sample from the fetus or a sample of amniotic fluidSince 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 blackapplicants 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.[36]
Children born with sickle-cell disease will undergo close observation by the paediatrician and will requiremanagement by a haematologist to assure they remain healthy. These patients will take a 1 mg dose of folic aciddaily for life. From birth to five years of age, they will also have to take penicillin daily due to the immatureimmune system that makes them more prone to early childhood illnesses.
[edit] Malaria chemoprophylaxis
The protective effect of sickle cell trait does not apply to people with sickle cell disease; in fact, they areuniquely vulnerable to malaria, since the most common cause of painful crises in malarial countries is infectionwith malaria. It has therefore been recommended that people with sickle cell disease living in malarial countriesshould receive anti-malarial chemoprophylaxis for life.[37]
[edit] Vaso-occlusive crisis
Most people with sickle-cell disease have intensely painful episodes called vaso-occlusive crises. Thefrequency, severity, and duration of these crises, however, vary tremendously. Painful crises are treatedsymptomatically with analgesics; pain management requires opioid administration at regular intervals until thecrisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac ornaproxen). 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 effectiveagent that is frequently prescribed by doctors in order to help control any itching associated with the use of opioids.
[edit] Acute chest crisis
Management is similar to vaso-occlusive crisis, with the addition of antibiotics (usually a quinolone ormacrolide, since wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome),[38] oxygensupplementation for hypoxia, and close observation. Should the pulmonary infiltrate worsen or the oxygenrequirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves theexchange of a significant portion of the patients red cell mass for normal red cells, which decreases the percentof haemoglobin S in the patient's blood.
[edit] Hydroxyurea
The first approved drug for the causative treatment of sickle-cell anaemia, hydroxyurea, was shown to decreasethe number and severity of attacks in a study in 1995 (Charache et al.)[39] and shown to possibly increase
survival time in a study in 2003 (Steinberg et al.).[40]
This is achieved, in part, by reactivating fetal haemoglobinproduction in place of the haemoglobin S that causes sickle-cell anaemia. Hydroxyurea had previously beenused as a chemotherapy agent, and there is some concern that long-term use may be harmful, but this risk hasbeen shown to be either absent or very small and it is likely that the benefits outweigh the risks.[41]
[edit] Transfusion therapy
Blood transfusions are often used in the management of sickle cell disease in acute cases and to preventcomplications by decreasing the the number of red blood cells (RBC) that can sickle by adding normal redblood cells.[42] In children prophylactic chronic red blood cell (RBC) transfusion therapy has been shown to be
efficacious to a certain extent in reducing the risk of first stroke or silent stroke when transcranial Doppler (TCD) ultrasonography shows abnormal increased cerebral blood flow velocities. In those who have sustained aprior stoke event it also reduces the risk of recurrent stroke and additional silent strokes .[43][44]
[edit] Bone marrow transplants
Bone marrow transplants have proven to be effective in children.[45]
[edit ] History
This collection of clinical findings was unknown until the explanation of the sickle cells in 1910 by the Chicagocardiologist 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 inDecember 1904 suffering from anaemia.[46]
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 ofpneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada.[47] Herrick'spublished account included illustrations, but the earliest available slide showing sickle cells is that of a 1918autopsy from a soldier with sickle trait, initially reviewed only 92 years later.[48]
The disease was named "sickle-cell anemia" by Verne Mason in 1922, then a medical resident at Johns HopkinsHospital.[49] 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 historyof the condition tracked reports back to 1670 in one Ghanaian family.[50] Also, the practice of using tar soap tocover blemishes caused by sickle-cell sores was prevalent in the black community. [citation needed ]
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 mutationof a specific protein, a milestone in the history of molecular biology, and it was published in their paper "SickleCell Anemia, a Molecular Disease".
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equalnumber of copies of the chromosome in males and females.[1] For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y. So, humans have 23pairs of chromosomes.
Human chromosomes
Female (XX) Male (XY)
There are two copies of each autosome (chromosomes 1-22) in both females and males. The sex chromosomes
are different: There are two copies of the X-chromosome in females, but males have a single X-chromosome
and a Y-chromosome.
In genetics, the term "recessive gene" refers to an allele that causes a phenotype (visible or detectablecharacteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele)and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes,one from mother and one from father. If a genetic trait is recessive, a person needs to inherit two copies of thegene for the trait to be expressed. Thus, both parents have to be carriers of a recessive trait in order for a child toexpress that trait. If both parents are carriers, there is a 25% chance with each child to show the recessive trait.Thus if the parents are closely related (in-breeding) the probability of both having inherited the same gene isincreased and as a result the probability of the children showing the recessive trait is increased as well.
The term "recessive gene" is part of the laws of Mendelian inheritance created by Gregor Mendel. Examples of recessive genes in Mendel's famous pea plant experiments include those that determine the color and shape of seed pods, and plant height.
Autosomal recessive or autorecessive is a mode of inheritance of genetic traits located on the autosomes (the22 non-sex determining chromosomes).
In opposition to autosomal dominant trait, a recessive trait only becomes phenotypically apparent when twocopies of a gene (two alleles) are present. In other words, the subject is homozygous for the trait. Recessivegenes will also show a horizontal inheritance on a pedigree chart. The frequency of the carrier state can becalculated by the Hardy-Weinberg formula: p2 + 2 pq + q
2 = 1 ( p is the frequency of one pair of alleles, andq = 1 − p is the frequency of the other pair of alleles.)
Recessive genetic disorders occur when both parents are carriers and each contributes an allele to the embryo.
As both parents are heterozygous for the disorder, the chance of two disease alleles being inherited by one of their offspring is 25% (in autosomal dominant traits this is higher). 50% of the children (or 2/3 of the remainingones) are carriers. When one of the parents is homozygous, the trait will only show in his/her offspring if theother parent is also a carrier. In that case, the chance of disease in the offspring is 50%.
Fitness (often denoted w in population genetics models) is a central idea in evolutionary theory. It can bedefined either with respect to a genotype or to a phenotype in a given environment. In either case, it describesthe ability to both survive and reproduce, and is equal to the average contribution to the gene pool of the nextgeneration that is made by an average individual of the specified genotype or phenotype. If differences betweenalleles at a given gene affect fitness, then the frequencies of the alleles will change over generations; the alleleswith higher fitness become more common. This process is called natural selection.
An individual's fitness is manifested through its phenotype. The phenotype is affected by the developmentalenvironment as well as by genes, and the fitness of a given phenotype can be different in differentenvironments. The fitnesses of different individuals with the same genotype are therefore not necessarily equal.However, since the fitness of the genotype is an averaged quantity, it will reflect the reproductive outcomes of all individuals with that genotype in a given environment or set of environments.
Inclusive fitness differs from individual fitness by including the ability of an allele in one individual to promotethe survival and/or reproduction of other individuals that share that allele, in preference to individuals with adifferent allele. One mechanism of inclusive fitness is kin selection.
Fitness is often defined as a propensity or probability, rather than the actual number of offspring. For example,according to Maynard Smith, "Fitness is a property, not of an individual, but of a class of individuals – forexample homozygous for allele A at a particular locus. Thus the phrase ’expected number of offspring’ means
the average number, not the number produced by some one individual. If the first human infant with a gene forlevitation were struck by lightning in its pram, this would not prove the new genotype to have low fitness, butonly that the particular child was unlucky." [1] Equivalently, "the fitness of the individual - having an array x of phenotypes - is the probability, s(x), that the individual will be included among the group selected as parents of the next generation."[2]
[edit ] Measures of fitness
There are two commonly used measures of fitness; absolute fitness and relative fitness.
[edit] Absolute fitness
Absolute fitness (wabs) of a genotype is defined as the ratio between the number of individuals with thatgenotype after selection to those before selection. It is calculated for a single generation and may be calculatedfrom absolute numbers or from frequencies. When the fitness is larger than 1.0, the genotype increases infrequency; a ratio smaller than 1.0 indicates a decrease in frequency.
Absolute fitness for a genotype can also be calculated as the product of the proportion surviving times theaverage fecundity.
[edit] Relative fitness
Relative fitness is quantified as the average number of surviving progeny of a particular genotype compared
with average number of surviving progeny of competing genotypes after a single generation, i.e. one genotypeis normalized at w = 1 and the fitnesses of other genotypes are measured with respect to that genotype. Relativefitness can therefore take any nonnegative value, including 0.
The two concepts are related, as can be seen by dividing each by the mean fitness, which is weighted bygenotype frequencies.
Because fitness is a coefficient, and a variable may be multiplied by it several times, biologists may work with"log fitness" (particularly so before the advent of computers). By taking the logarithm of fitness each term maybe added rather than multiplied.
Dominance in genetics is a relationship between two variant forms (alleles) of a single gene, in which one allele masks
the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms ( A & B), three
combinations of alleles (genotypes) are possible: AA, AB, and BB. If AA and BB individuals (homozygotes) show different
forms of the trait (phenotype), and AB individuals (heterozygotes) show the same phenotype as AA individuals, then
allele A is said to dominate or be dominant to allele B, and B is said to be recessive to A. If instead AB has the same
Most familiar plants, like peas, and familiar animals, like fruit flies and humans, have paired chromosomes, andare described as diploid. One chromosome of each pair is contributed by each parent: one by the female parentin her ovum, and one by the male parent in his sperm, which are joined at fertilization. The ovum and spermcells have only one copy of each chromosome and are described as haploid. Production of haploid gametes occurs through a process called meiosis.
[edit] Chromosomes, genes, and alleles
Each chromosome of a matching pair is structurally similar to the other, and each member of a homologous pairhas the same genetic material arranged in the same order and physical locations (loci, singular locus). Thegenetic material in each chromosome comprises a series of discrete genes that influence various traits. Thus,each gene also has a corresponding homologue, which may exist in different forms: the variant forms are calledalleles. The alleles at the same locus on the two homologous chromosomes may be identical or different.
In popular usage, "gene" and "allele" are often used interchangeably. This produces misunderstandings.Properly, "gene" refers to a hereditary unit, ordinarily at a fixed position on a chromosome, that influences aparticular trait. Genes are now understood to comprise DNA. "Allele" refers to any of the many particular formsof a gene that may be present in a population of individuals from a particular species, at a particular locus. E.g.,it is inaccurate to say "This pea plant has a pair of wrinkled genes", and it is more accurate to say, "This plant
has two 'w' alleles for the 'Seed Shape' gene, and will produce wrinkled peas." Consider also the example of blood type in humans. Near the long arm of chromosome nine appears a gene that determines whether anindividual will be blood type, A, B, or O. There are three different alleles that could be present at this locus, butonly two can be present in any individual, one inherited from their mother and one from their father .[1]
[edit] Homozygous, heterozygous
If two alleles of a given gene are identical, the organism is called a homozygote and is homozygous with respectto that gene; if instead the two alleles are different, the organism is a heterozygote and is heterozygous. Thegenetic makeup of an organism, either at a single locus or over all its genes collectively, is called the genotype. The genotype of an organism directly or indirectly affects its molecular, physical,and other traits, which
individually or collectively are called the phenotype. At heterozygous gene loci, the two alleles interact toproduce the phenotype. The simplest form of allele interaction is the one described by Mendel, now calledMendelian, in which the appearance/phenotype caused by one allele is apparent, called dominant, and theappearance/phenotype caused by the other allele is not apparent, called recessive.
In the simplest case, the phenotypic effect of one allele completely masks the other in heterozygouscombination; that is, the phenotype produced by the two alleles in heterozygous combination is identical to thatproduced by one of the two homozygous genotypes. The allele that masks the other is said to be dominant to thelatter, and the alternative allele is said to be recessive to the former.[2]
[edit] Which trait is dominant?
The terms dominant and recessive refer to the interaction of alleles in producing the phenotype of theheterozygote. If there are two alternative phenotypes, by definition the phenotype exhibited by the heterozygoteis called "dominant" and the "hidden" phenotype is called "recessive". The key concept of dominance is that theheterozygote is phenotypically identical to one of the two homozygotes. That trait corresponding to thedominant allele may then be called the "dominant" trait.
Dominance is a genotypic relationship between alleles, as manifested in the phenotype. It is unrelated to thenature of the phenotype itself, e.g., whether it is regarded as normal or abnormal, standard or nonstandard,healthy or diseased, stronger or weaker, or more or less extreme. It is also important to distinguish between the
"round" gene locus, the "round" allele at that locus, and the "round" phenotype it produces. It is inaccurate tosay that "the round gene dominates the wrinkled gene" or that "round peas dominate wrinkled peas."
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