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Sickle Cell Anemia* - Biology

Sickle Cell Anemia* - Biology



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Sickle Cell Anemia: A look at the connection between DNA and Phenotype

Genes are translated into proteins, mutations often (but not always) result in changes in the sequence of amino acids in those proteins. One of the best examples of this phenomenon can be observed when mutations occur in the gene for one of the protein components of the red blood cell protein we call hemoglobin.

A major component of the erythrocytes (red blood cells) found in ver­tebrates is hemoglobin. A molecule of hemoglobin from a normal adult human contains 4 proteins (two identical alpha polypeptides and two identical beta polypeptides) surrounding a core of heme (contains complex molecule containing an atom of iron which can combine reversibly with oxygen). Thus, hemoglobin functions as the major oxygen-carrying constituent of blood. Because of hemoglobin, a given volume of blood can carry far more oxygen than could be dissolved in an equal volume of water.
In many human populations, particularly those with origins in Central Africa or the Mediterranean, there are individuals who suffer from severe anemia and whose blood contains numerous distorted, sickle-shaped erythrocytes. Hence, the disease was given the name sickle-cell anemia.

Figure 1: Notice the sickle shaped cells in the image. By Dr Graham Beards via Wikimedia Commons

Biochemical studies established that the gene affected in sickle-cell ane­mia has the code for an abnormal beta polypeptide, which is one of the components of the hemoglobin molecule. Therefore, there are two different forms of the hemoglobin gene that codes for the beta chain:
Form 1: HbA has the code for a normal beta chain
Form 2: HbS has the code for an abnormal beta chain

Humans are diploid organisms; they have two copies of most genes. However, the two copies they possess do not have to be identical. When there are two possible alleles for a gene (such as in the gene for the beta chain of hemoglobin), a diploid individual will have one of three possible combinations of the two alleles. They can be HbA HbA , HbA HbS, or HbSHbS.

The set of alleles present in an individual for a given gene is known as the individual’s genotype. The three combinations of two alleles above are therefore the three different genotypes. Individuals that have two copies of the same allele are called homozygous; individuals with two different alleles are called heterozygous. So, an individual that is HbA HbAis homozygous normal beta chain, an individual that is HbA HbS is heterozygous, and an individual that is HbS HbS is homozygous abnormal beta chain.
It is the homozygous HbS individuals that contain sickle shaped blood cells.

Mechanism of the Disease

In the capillaries (microscopic blood vessels that directly exchange oxygen with the tissues), erythrocytes can be subjected to low oxygen tension after they lose their oxygen to the surrounding tissues. In this low oxygen situation, the abnormal hemoglobin molecules of HbS HbS individuals tend to polymerize (join together), forming stiff, tubular fibers which ultimately distort the shape of the entire erythrocyte, giving it the characteristic “sickle” shape. These sickled cells have a number of effects on the body via two processes.

1. Sickled cells are less able to enter and move through the capillaries.
Once in the capillaries, they clog capillary flow and cause small blood clots. Reduced blood flow results in reduced oxygen availability to the tissues. Reduced oxygen supply results in tissue death and damage to vital organs (e.g., the heart, liver and spleen).
2. Sickled blood cells have a shorter lifespan than normal red blood cells:
Reduced lifespan of erythrocytes places a greater demand on the bone marrow to make new red blood cells and on the spleen to break down dead erythrocytes. Increased demand on the bone marrow results in severe pain in the long bones and joints. Individuals suffering from sickle-cell anemia are frequently ill and generally have a considerably reduced lifespan. These individuals are said to have sickle-cell disease.

Heterozygous individuals (HbA HbS) are said to be carriers for sickle-cell anemia. Note: this is a specific term and is not the same thing as sickle cell anemia—heterozygotes do not have the disease themselves but their children may inherit the condition. Carriers have no anemia, do have good health (as do HbA HbA individuals) and their erythrocytes maintain normal shape in the blood. In other words, they are phenotypically normal under most conditions, and probably do not know that they “carry” the HbS allele. However, if heterozygotes are exposed to condi­tions of low oxygen levels (such as strenuous activity at high altitudes) some of their erythrocytes do sickle. Red blood cells in blood samples of heterozygotes subjected to greatly reduced oxygen tension in the laboratory also sickle.

Why is sickle cell anemia most prevalent in people with origins in Central Africa and the Mediterranean? If you look at the figure below (Figure 2), you will see the occurrence of sickle cell anemia overlaps with the pervasiveness of malaria. This seems odd, but those individuals how are heterozygous (HbA HbS) for the sickle cell allele are less likely to contract and die from malaria then those who are homozygous (HbA HbA). The HbS polypeptide that is produced by the heterozygous individual stops the organism (Plasmodium) that causes malaria from invading the red blood cells. So, in areas where malaria is common there is selection pressure for the HbS allele, and the HbS allele occurs in a higher frequency because the those who have one copy of the HbS allele will live longer and have more children. In areas where malaria is not common, there is selection pressure against the HbS allele, and the HbS allele occurs in a lower frequency. As you will learn in a later chapter, there is an 25% chance that two carriers will have a child who is homozygous HbS HbS), and this child will pay the evolutionary price for the protection from malaria that the parents were afforded. It seems to be in this way that evolution by natural selection retains such a potentially detrimental allele in a population. The sickle cell example is only one of what is called heterozygous advantage, we have provided a number of other examples in Table 1.

Figure 2: The hatched line represents the distribution of malaria. The various red colors represent the relative frequency of sickle cell allele in the population with the dark red having the highest frequency and the light red having the lowest frequency. Work by Eva Horne.

Distribution of malaria and the frequency of sickle cell allele

TABLE 1: Examples of Heterozygous Advantage in Humans
Recessive IllnessHeterozygote AdvantagePossible Explanation
Cystic fibrosisprotection against diarrheal diseases such as choleraCarriers have too few functional chloride channels in intestinal cells, blocking toxin
G6PD DeficiencyProtection against malariaRed blood cells inhospitable to malaria
Phenylketonuria (PKU)Protection against miscarriage induced by a fungal toxinExcess amino acid (phenylalanine) in carriers inactivates toxin
Tay-Sachs diseaseProtection against tuberculosisUnknown
Noninsulin-dependent diabetes mellitusProtection against starvationTendency to gain weight protects against starvation during famine

Sickle Cell Anemia

Sickle cell anemia occurs in 1 in 500 individuals of African descent and is characterized by red blood cells that are rigid and sickled in shape (see Figure 3).

The difficulty these sickle cells have in moving through the circulatory system has numerous effects on those who suffer from the disease including anemia, brain damage, and kidney failure (effects are further illustrated in Figure 4).

Believe or not, all of the symptoms listed in the figure above are caused by a single point mutation in codon six of the b -globin gene from glutamic acid to valine (See figure below). This small difference produces a mutant protein that is insoluble in the red blood cell, and consequently, forms a crystalline structure.

There are, however, advantages to carrying only one copy of the mutant b -globin gene. These heterozygote individuals do not suffer from the disease and exhibit increased resistance to malaria because the parasite which causes the disease is unable to reproduce in the red blood cells of heterozygote individuals. Malaria occurs most frequently in tropical regions near the equator which helps to explain why those of African descent are more commonly affected.

Considering the devastating effects of sickle cell anemia, parents may want to determine if they are carriers of the disease before they decide to have children. If two carriers mate, 25 percent of their children will be homozygous for the mutant gene. The use of restriction enzymes now enables carriers to be determined by examining RFLPs, or restriction fragment length polymorphisms. Mutations in DNA that add or delete a restrictions site can be determined by analysis using gel electrophoresis after digesting DNA with a restriction enzyme. First compare the restriction sites (shown in blue) found on the wild-type and mutant b -globin genes:

&zwnj

Notice that the point mutation in codon six eliminates one of the restriction sites normally found in the wild-type copy of the b -globin gene. If these two genes were digested with restriction enzyme and run out on a gel you would expect the following results:

Your instructor will use sickle cell anemia to illustrate how to use the various databases in this laboratory exercise. Click on the link below to return to the Bioinformatics Laboratory Homepage.


Sickle Cell Anemia* - Biology

I. What is Sickle Cell Anemia?

A gene is a segment of DNA that codes for a protein or a trait.. Genes can be any length and sometimes involve multiple sections of DNA. The HBB gene provides instructions for making a protein called Beta-globin which is part of a large protein called hemoglobin that is found in red blood cells. Each hemoglobin protein can carry four molecules of oxygen, which is delivered to the body's organs and tissues.

If a person doesn't have enough red blood cells or the cells don't work properly, organs can become deprived of oxygen. This condition is called anemia. A person with anemia may feel tired all the time, experience difficulty with breathing, leg cramps, and dizziness.

There is one type of anemia that is related to the shape of the HBB protein. When a person has sickle cell anemia, the hemoglobin protein forms long chains that change the shape of the red blood cell. Instead of a disc shaped structure that moves easily through blood vessels, sickled blood cells are shaped like bananas. The reason they have a sickled shape is because the underlying gene has the wrong instructions. These misshapen blood cells get clogged in vessels and don't have the life expectancy of normal blood cells. A person with sickle cell disease will experience fatigue (feeling tired) and have episodes of extreme pain, called a pain crisis. Sickled blood cells that block vessels in the brain can even cause stroke.

Sickle cell anemia is a life threatening disease that affects about 100,000 Americans. It is an inherited disease that is passed from parents to their children, but parents can be carriers of the gene and not have any symptoms. If both parents are carriers, their children have a 25% chance of having sickle cell anemia.

1. What is a gene? _________________________________________

2. What is hemoglobin? _________________________________________

3. How is a sickled blood cell different from a normal one? __________________________

4. Why are the blood cells the wrong shape? ___________________________

5. What are the symptoms of sickle cell anemia? ___________________________

6. What is a carrier? ______________________________

II. How DNA Makes Protein

Recall that DNA contains four bases: Adenine, Guanine, Cytosine, and Thymine. The sequence of A's, T's, G's, and C's are what determines the protein that is built. Each set of three bases will code for a single amino acid. Proteins are simply chains of amino acids. To make proteins, DNA must send its code sequence to the ribosomes in the cell, but it needs a messenger to do that. Transcription is the process where DNA is converted to a molecule of messenger RNA (mRNA). The mRNA is then used to build a protein like hemoglobin.

CODON CHART

To determine the amino acid sequence of the gene, you must transcribe the DNA to RNA. The base pair rule is used to create RNA, but RNA does not contain thymine, it contains URACIL instead. This is why codon charts have U's in them and no T's.

A codon chart tells you what bases in RNA code for what amino acids. The ribosome combines all the amino acids to create a single protein, like hemoglobin. It takes three bases to determine one amino acid. Amino acids are usually abbreviated. GUC makes the amino acid valine, abbreviated as "Val" on the chart.

Here is how the codon chart could be used to determine the amino acid sequence:

DNA: A A T C A G → (DNA sequence of gene)
RNA: U U A G U C (transcribed from RNA follow base pair rule, no T's)
Amino Acids: Leu Val (find on codon chart)

7. In order to make a protein, the message on DNA must be converted to what? ___________

8. How many bases in DNA are needed to code for a single amino acid? _________

9. What is a protein? _________________________________________________

10. . What base is found in RNA, but not DNA? ________

11. Consider the sequence shown, determine the complementary RNA and the amino acids

DNA T A C G T A T T T G C A C A C
RNA
Amino Acids

III. A Change in DNA Can Change the Protein

Sometimes, one of the letters in DNA gets switched with another letter, causing a mutation in the DNA. Many mutations don't have any effects, but some will change the amino acid made by the ribosomes. In the case of sickle cell anemia, just a single letter change alters the shape of the hemoglobin protein.

12. Use the codon chart to determine the amino acids created from each DNA.

13. What codon in the sickle cell DNA is altered? ___________________ (1st, 2nd, or 3rd)

14. What happens in people that have this difference in their DNA? ____________________

15. Explain how it would be possible to have a change in a single base of DNA, but have the protein NOT change and be functional. Hint: look at the codon chart.

TED-Ed Video on Sickle Cell (

/>This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.


Sickle Cell Anemia* - Biology

Abstract

Sickle cell anemia is the most common form of sickle cell disease (SCD). SCD is a serious disorder in which the body makes sickle-shaped red blood cells. &ldquoSickle-shaped&rdquo means that the red blood cells are shaped like a crescent.

Normal red blood cells are disc-shaped and look like doughnuts without holes in the center. They move easily through your blood vessels. Red blood cells contain an iron-rich protein called hemoglobin. This protein carries oxygen from the lungs to the rest of the body.Sickle cells contain abnormal hemoglobin called sickle hemoglobin or hemoglobin S. Sickle hemoglobin causes the cells to develop a sickle, or crescent, shape.

Sickle cells are stiff and sticky. They tend to block blood flow in the blood vessels of the limbs and organs. Blocked blood flow can cause pain and organ damage. It can also raise the risk for infection.

Normal Red Blood Cells and Sickle Cells

Figure A shows normal red blood cells flowing freely in a blood vessel. The inset image shows a cross-section of a normal red blood cell with normal hemoglobin. Figure B shows abnormal, sickled red blood cells blocking blood flow in a blood vessel. The inset image shows a cross-section of a sickle cell with abnormal (sickle) hemoglobin forming abnormal strands.

Sickle Cell Mutation

Sickle cell anemia has no widely available cure. However, treatments to improve the anemia and lower complications can help with the symptoms and complications of the disease in both children and adults. Blood and marrow stem cell transplants may offer a cure for a small number of people.

Over the past 100 years, doctors have learned a great deal about sickle cell anemia. They know its causes, how it affects the body, and how to treat many of its complications.
Sickle cell anemia varies from person to person. Some people who have the disease have chronic (long-term) pain or fatigue (tiredness). However, with proper care and treatment, many people who have the disease can have improved quality of life and reasonable health much of the time.

Because of improved treatments and care, people who have sickle cell anemia are now living into their forties or fifties, or longer.

What Causes Sickle Cell Anemia?

Sickle cell anemia is an inherited disease. People who have the disease inherit two genes for sickle hemoglobin&mdashone from each parent.

Sickle hemoglobin causes red blood cells to develop a sickle, or crescent, shape. Sickle cells are stiff and sticky. They tend to block blood flow in the blood vessels of the limbs and organs. Blocked blood flow can cause pain and organ damage. It can also raise the risk for infection.

Sickle Cell Trait

People who inherit a sickle hemoglobin gene from one parent and a normal gene from the other parent have sickle cell trait. Their bodies make both sickle hemoglobin and normal hemoglobin.

People who have sickle cell trait usually have few, if any, symptoms and lead normal lives. However, some people may have medical complications.

People who have sickle cell trait can pass the sickle hemoglobin gene to their children. The following image shows an example of an inheritance pattern for sickle cell trait.
Example of an Inheritance Pattern for Sickle Cell Trait

When both parents have a normal gene and an abnormal gene, each child has a 25 percent chance of inheriting two normal genes a 50 percent chance of inheriting one normal gene and one abnormal

What Are the Signs and Symptoms of Sickle Cell Anemia

The signs and symptoms of sickle cell anemia vary. Some people have mild symptoms. Others have very severe symptoms and often are hospitalized for treatment.Sickle cell anemia is present at birth, but many infants don't show any signs until after 4 months of age.The most common signs and symptoms are linked to anemia and pain. Other signs and symptoms are linked to the disease's complications.

Signs and Symptoms Related to Anemia

The most common symptom of anemia is fatigue (feeling tired or weak). Other signs and symptoms of anemia include:

&bull Coldness in the hands and feet

&bull Paler than normal skin or mucous membranes (the tissue that lines your nose, mouth, and other organs and body cavities)

&bull Jaundice (a yellowish color of the skin or whites of the eyes)

Signs and Symptoms Related to Pain

Sudden pain throughout the body is a common symptom of sickle cell anemia. This pain is called a sickle cell crisis. Sickle cell crises often affect the bones, lungs, abdomen, and joints.

These crises occur when sickled red blood cells block blood flow to the limbs and organs. This can cause pain and organ damage.The pain from sickle cell anemia can be acute or chronic, but acute pain is more common. Acute pain is sudden and can range from mild to very severe. The pain usually lasts from hours to as long as a week or more.Many people who have sickle cell anemia also have chronic pain, especially in their bones. Chronic pain often lasts for weeks or months and can be hard to bear and mentally draining. Chronic pain may limit your daily activities.

Almost all people who have sickle cell anemia have painful crises at some point in their lives. Some have these crises less than once a year. Others may have crises once a month or more. Repeated crises can damage the bones, kidneys, lungs, eyes, heart, and liver. This type of damage happens more often in adults than in children.Many factors can play a role in sickle cell crises. Often, more than one factor is involved and the exact cause isn't known.

You can control some factors. For example, the risk of a sickle cell crisis increases if you're dehydrated (your body doesn't have enough fluids). Drinking plenty of fluids can lower the risk of a painful crisis.You can't control other factors, such as infections.Painful crises are the leading cause of emergency room visits and hospital stays for people who have sickle cell anemia.

Complications of Sickle Cell Anemia

Sickle cell crises can affect many parts of the body and cause many complications.

Hand-Foot Syndrome

Sickle cells can block the small blood vessels in the hands and feet in children (usually those younger than 4 years of age). This condition is called hand-foot syndrome. It can lead to pain, swelling, and fever.Swelling often occurs on the back of the hands and feet and moves into the fingers and toes. One or both hands and/or feet might be affected at the same time.

Splenic Crisis

The spleen is an organ in the abdomen. Normally, it filters out abnormal red blood cells and helps fight infections. Sometimes the spleen may trap red blood cells that should be in the bloodstream. This causes the spleen to grow large and leads to anemia.If the spleen traps too many red blood cells, you may need blood transfusionsuntil your body can make more cells and recover.

Infections

Both children and adults who have sickle cell anemia may get infections easily and have a hard time fighting them. This is because sickle cell anemia can damage the spleen, an organ that helps fight infections.

Infants and young children who have damaged spleens are more likely to get serious infections that can kill them within hours or days. Bloodstream infections are the most common cause of death in young children who have sickle cell anemia.Medicines and vaccines can help prevent severe illness and death. For example, vaccines are available for infections such as meningitis, influenza, and hepatitis.

Getting treatment right away for high fevers (which can be a sign of a severe infection) also helps prevent death in infants and children who have sickle cell anemia.It's also important to get treatment right away for a cough, problems breathing, bone pain, and headaches.

Acute Chest Syndrome

Acute chest syndrome is a life-threatening condition linked to sickle cell anemia. This syndrome is similar to pneumonia. An infection or sickle cells trapped in the lungs can cause acute chest syndrome.People who have this condition often have chest pain, shortness of breath, and fever. They also often have low oxygen levels and abnormal chest X ray results.

Pulmonary Hypertension

Damage to the small blood vessels in the lungs makes it hard for the heart to pump blood through the lungs. This causes blood pressure in the lungs to rise.Increased blood pressure in the lungs is called pulmonary hypertension (PH). Shortness of breath and fatigue are the main symptoms of PH.

Delayed Growth and Puberty in Children

Children who have sickle cell anemia often grow more slowly than other children. They may reach puberty later. A shortage of red blood cells causes the slow growth rate. Adults who have sickle cell anemia often are slender or smaller in size than other adults.

Stroke

Two forms of stroke can occur in people who have sickle cell anemia. One form occurs if a blood vessel in the brain is damaged and blocked. This type of stroke occurs more often in children than adults. The other form of stroke occurs if a blood vessel in the brain bursts.Either type of stroke can cause learning problems and lasting brain damage, long-term disability, paralysis (an inability to move), or death.

Eye Problems

Sickle cells also can affect the small blood vessels that deliver oxygen-rich blood to the eyes. Sickle cells can block these vessels or cause them to break open and bleed. This can damage the retinas&mdashthin layers of tissue at the back of the eyes. The retinas take the images you see and send them to your brain.This damage can cause serious problems, including blindness.

Priapism

Males who have sickle cell anemia may have painful, unwanted erections. This condition is called priapism. It happens because the sickle cells block blood flow out of an erect penis. Over time, priapism can damage the penis and lead to impotence.

Gallstones

When red blood cells die, they release their hemoglobin. The body breaks down this protein into a compound called bilirubin. Too much bilirubin in the body can cause stones to form in the gallbladder, called gallstones.Gallstones may cause steady pain that lasts for 30 minutes or more in the upper right side of the belly, under the right shoulder, or between the shoulder blades. The pain may happen after eating fatty meals.

People who have gallstones may have nausea (feeling sick to the stomach), vomiting, fever, sweating, chills, clay-colored stools, or jaundice.

Ulcers on the Legs

Sickle cell ulcers (sores) usually begin as small, raised, crusted sores on the lower third of the leg. Leg sores may occur more often in males than in females. These sores usually develop in people who are aged 10 years or older.The cause of sickle cell ulcers isn't clear. The number of ulcers can vary from one to many. Some heal quickly, but others persist for years or come back after healing.

Multiple Organ Failure

Multiple organ failure is rare, but serious. It happens if you have a sickle cell crisis that causes two out of three major organs (lungs, liver, or kidneys) to fail. Often, multiple organ failure occurs during an unusually severe pain crisis.Symptoms of this complication are fever, rapid heartbeat, problems breathing, and changes in mental status (such as sudden tiredness or confusion).

How is Sickle Cell Anemia Diagnosed?

A simple blood test, done at any time during a person's lifespan, can detect whether he or she has sickle hemoglobin. However, early diagnosis is very important.

In the United States, all States mandate testing for sickle cell anemia as part of their newborn screening programs. The test uses blood from the same blood samples used for other routine newborn screening tests. The test can show whether a newborn infant has sickle hemoglobin.Test results are sent to the doctor who ordered the test and to the baby's primary care doctor. It's important to give the correct contact information to the hospital. This allows the baby's doctor to get the test results as quickly as possible.

Health providers from a newborn screening followup program may contact you directly to make sure you're aware of the test results.If the test shows some sickle hemoglobin, a second blood test is done to confirm the diagnosis. The second test should be done as soon as possible and within the first few months of life.

The primary care doctor may send you to a hematologist for a second blood test. A hematologist is a doctor who specializes in blood diseases and disorders. This doctor also can provide treatment for sickle cell disease if needed.

Doctors also can diagnose sickle cell disease before birth. This is done using a sample of amniotic fluid or tissue taken from the placenta. (Amniotic fluid is the fluid in the sac surrounding a growing embryo. The placenta is the organ that attaches the umbilical cord to the mother's womb.)Testing before birth can be done as early as 10 weeks into the pregnancy. This testing looks for the sickle hemoglobin gene, rather than the abnormal hemoglobin that the gene makes.

New Treatments

Research on blood and marrow stem cell transplants, gene therapy, and new medicines for sickle cell anemia is ongoing. The hope is that these studies will provide better treatments for the disease. Researchers also are looking for a way to predict the severity of the disease.

Blood and Marrow Stem Cell Transplant

A blood and marrow stem cell transplant can work well for treating sickle cell anemia. This treatment may even offer a cure for a small number of people.The stem cells used for a transplant must come from a closely matched donor. The donor usually is a close family member who doesn't have sickle cell anemia. This limits the number of people who may have a donor.

The transplant process is risky and can lead to serious side effects or even death. However, new transplant approaches may improve treatment for people who have sickle cell anemia and involve less risk.Blood and marrow stem cell transplants usually are used for young patients who have severe sickle cell anemia. However, the decision to give this treatment is made on a case-by-case basis.

Researchers continue to look for sources of bone marrow stem cells&mdashfor example, blood from babies' umbilical cords. They also continue to look for ways to reduce the risks of this procedure.

Gene Therapy

Gene therapy is being studied as a possible treatment for sickle cell anemia. Researchers want to know whether a normal gene can be put into the bone marrow stem cells of a person who has sickle cell anemia. This would cause the body to make normal red blood cells.

Researchers also are studying whether they can "turn off" the sickle hemoglobin gene or "turn on" a gene that makes red blood cells behave normally.

New Medicines

Researchers are studying several medicines for sickle cell anemia. They include:

&bull Decitabine: Like hydroxyurea, this medicine prompts the body to make fetal hemoglobin. Fetal hemoglobin helps prevent red blood cells from sickling and improves anemia. Decitabine might be used instead of hydroxyurea or added to hydroxyurea.

&bull Adenosine A2a receptor agonists: These medicines may reduce pain-related complications in people who have sickle cell anemia.

&bull 5-HMF: This natural compound binds to red blood cells and increases their oxygen. This helps prevent the red blood cells from sickling.

Take Steps To Prevent and Control Complications

Along with adopting healthy lifestyle habits, you can take other steps to prevent and control painful sickle cell crises. Many factors can cause sickle cell crises. Knowing how to avoid or control these factors can help you manage your pain.You may want to avoid decongestants, such as pseudoephedrine. These medicines can tighten blood vessels, making it harder for red blood cells to move smoothly through the vessels.

Avoid extremes of heat and cold. Wear warm clothes outside in cold weather and inside of air-conditioned rooms. Don't swim in cold water. Also, be cautious at high altitudes you may need extra oxygen.If possible, avoid jobs that require a lot of heavy physical labor, expose you to extremes of heat or cold, or involve long work hours.

Don't travel in airplanes in which the cabins aren't pressurized (that is, no extra oxygen is pumped into the cabin). If you must travel in such an airplane, talk with your doctor about how to protect yourself.

Ongoing Care

Get a flu shot and other vaccines to prevent infections. You also should see your dentist regularly to prevent infections and loss of teeth. Contact your doctor right away if you have any signs of an infection, such as a fever or trouble breathing.For people who have sickle cell anemia, just like for everyone else, regular medical care and treatment for health issues are important. Your checkups may include extra tests for possible kidney, lung, and liver diseases. See a sickle cell anemia expert regularly. Also, see an eye doctor regularly to check for damage to your eyes.

Learn the signs and symptoms of a stroke. They include:

&bull Paralysis (an inability to move) or numbness of the face, arms, or legs, especially on one side of the body

&bull Trouble speaking or understanding speech

&bull Trouble seeing in one or both eyes

&bull Dizziness, trouble walking, loss of balance or coordination, and unexplained falls

&bull Sudden and severe headache

If you think you&rsquore having a stroke, call 9&ndash1&ndash1 right away. Do not drive to the hospital or let someone else drive you. Call an ambulance so that medical personnel can begin life-saving treatment on the way to the emergency room.

Get treatment and control any other medical conditions you have, such as diabetes.Talk with your doctor if you're pregnant or planning to become pregnant. Sickle cell anemia can worsen during pregnancy. You'll need special prenatal care.

Women who have sickle cell anemia also are at increased risk for an early birth or a low-birth-weight baby. However, with early prenatal care and frequent checkups, you can have a healthy pregnancy.


Sickle cell disease is the most common inherited blood disorder in the United States. Approximately 100,000 Americans have the disease.

In the United States, sickle cell disease is most prevalent among African Americans. About one in 12 African Americans and about one in 100 Hispanic Americans carry the sickle cell trait, which means they are carriers of the disease.

Sickle cell disease is caused by a mutation in the hemoglobin-Beta gene found on chromosome 11. Hemoglobin transports oxygen from the lungs to other parts of the body. Red blood cells with normal hemoglobin (hemoglobin-A) are smooth and round and glide through blood vessels.

In people with sickle cell disease, abnormal hemoglobin molecules - hemoglobin S - stick to one another and form long, rod-like structures. These structures cause red blood cells to become stiff, assuming a sickle shape. Their shape causes these red blood cells to pile up, causing blockages and damaging vital organs and tissue.

Sickle cells are destroyed rapidly in the bodies of people with the disease, causing anemia. This anemia is what gives the disease its commonly known name - sickle cell anemia.

The sickle cells also block the flow of blood through vessels, resulting in lung tissue damage that causes acute chest syndrome, pain episodes, stroke and priapism (painful, prolonged erection). It also causes damage to the spleen, kidneys and liver. The damage to the spleen makes patients - especially young children - easily overwhelmed by bacterial infections.

A baby born with sickle cell disease inherits a gene for the disorder from both parents. When both parents have the genetic defect, there's a 25 percent chance that each child will be born with sickle cell disease.

If a child inherits only one copy of the defective gene (from either parent), there is a 50 percent chance that the child will carry the sickle cell trait. People who only carry the sickle cell trait typically don't get the disease, but can pass the defective gene on to their children.

New Treatments Prolong Life:

Until recently, people with sickle cell disease were not expected to survive childhood. But today, due to preventive drug treatment, improved medical care and aggressive research, half of sickle cell patients live beyond 50 years.

Treatments for sickle cell include antibiotics, pain management and blood transfusions. A new drug treatment, hydroxyurea, which is an anti-tumor drug, appears to stimulate the production of fetal hemoglobin, a type of hemoglobin usually found only in newborns. Fetal hemoglobin helps prevent the "sickling" of red blood cells. Patients treated with hydroxyurea also have fewer attacks of acute chest syndrome and need fewer blood transfusions.

Bone Marrow Transplantation: The Only Cure:

Currently the only cure for sickle cell disease is bone marrow transplantation. In this procedure a sick patient is transplanted with bone marrow from healthy, genetically compatible sibling donors. However only about 18 percent of children with sickle cell disease have a healthy, matched sibling donor. Bone marrow transplantation is a risky procedure with many complications.

Gene Therapy Offers Promise of a Cure:

Researchers are experimenting with attempts to cure sickle cell disease by correcting the defective gene and inserting it into the bone marrow of those with sickle cell to stimulate production of normal hemoglobin. Recent experiments show promise.

Researchers used bioengineering to create mice with a human gene that produces the defective hemoglobin causing sickle cell disease. Bone marrow containing the defective hemoglobin gene was removed from the mice and genetically "corrected" by the addition of the anti-sickling human beta-hemoglobin gene. The corrected marrow was then transplanted into other mice with sickle cell disease. The genetically corrected mice began producing high levels of normal red blood cells and showed a dramatic reduction in sickled cells. Scientists are hopeful that the techniques can be applied to human gene transplantation using autologous transplantation, in which some of the patient's own bone marrow cells would be removed and genetically corrected.

Sickle cell disease is the most common inherited blood disorder in the United States. Approximately 100,000 Americans have the disease.

In the United States, sickle cell disease is most prevalent among African Americans. About one in 12 African Americans and about one in 100 Hispanic Americans carry the sickle cell trait, which means they are carriers of the disease.

Sickle cell disease is caused by a mutation in the hemoglobin-Beta gene found on chromosome 11. Hemoglobin transports oxygen from the lungs to other parts of the body. Red blood cells with normal hemoglobin (hemoglobin-A) are smooth and round and glide through blood vessels.

In people with sickle cell disease, abnormal hemoglobin molecules - hemoglobin S - stick to one another and form long, rod-like structures. These structures cause red blood cells to become stiff, assuming a sickle shape. Their shape causes these red blood cells to pile up, causing blockages and damaging vital organs and tissue.

Sickle cells are destroyed rapidly in the bodies of people with the disease, causing anemia. This anemia is what gives the disease its commonly known name - sickle cell anemia.

The sickle cells also block the flow of blood through vessels, resulting in lung tissue damage that causes acute chest syndrome, pain episodes, stroke and priapism (painful, prolonged erection). It also causes damage to the spleen, kidneys and liver. The damage to the spleen makes patients - especially young children - easily overwhelmed by bacterial infections.

A baby born with sickle cell disease inherits a gene for the disorder from both parents. When both parents have the genetic defect, there's a 25 percent chance that each child will be born with sickle cell disease.

If a child inherits only one copy of the defective gene (from either parent), there is a 50 percent chance that the child will carry the sickle cell trait. People who only carry the sickle cell trait typically don't get the disease, but can pass the defective gene on to their children.

New Treatments Prolong Life:

Until recently, people with sickle cell disease were not expected to survive childhood. But today, due to preventive drug treatment, improved medical care and aggressive research, half of sickle cell patients live beyond 50 years.

Treatments for sickle cell include antibiotics, pain management and blood transfusions. A new drug treatment, hydroxyurea, which is an anti-tumor drug, appears to stimulate the production of fetal hemoglobin, a type of hemoglobin usually found only in newborns. Fetal hemoglobin helps prevent the "sickling" of red blood cells. Patients treated with hydroxyurea also have fewer attacks of acute chest syndrome and need fewer blood transfusions.

Bone Marrow Transplantation: The Only Cure:

Currently the only cure for sickle cell disease is bone marrow transplantation. In this procedure a sick patient is transplanted with bone marrow from healthy, genetically compatible sibling donors. However only about 18 percent of children with sickle cell disease have a healthy, matched sibling donor. Bone marrow transplantation is a risky procedure with many complications.

Gene Therapy Offers Promise of a Cure:

Researchers are experimenting with attempts to cure sickle cell disease by correcting the defective gene and inserting it into the bone marrow of those with sickle cell to stimulate production of normal hemoglobin. Recent experiments show promise.

Researchers used bioengineering to create mice with a human gene that produces the defective hemoglobin causing sickle cell disease. Bone marrow containing the defective hemoglobin gene was removed from the mice and genetically "corrected" by the addition of the anti-sickling human beta-hemoglobin gene. The corrected marrow was then transplanted into other mice with sickle cell disease. The genetically corrected mice began producing high levels of normal red blood cells and showed a dramatic reduction in sickled cells. Scientists are hopeful that the techniques can be applied to human gene transplantation using autologous transplantation, in which some of the patient's own bone marrow cells would be removed and genetically corrected.


A SCHEMA FOR THE EVOLUTION OF THE HEMOGLOBINS

Our analysis of the amino acid sequences of adult and fetal human hemoglobin peptide chains led us to postulate an evolutionary scheme for the genes that control the peptide chains. Added to this understanding was the coemerging understanding of the close sequence and structural relationship between the monomeric myoglobin and the four-chain hemoglobins. We used a parsimonious model of sequence evolution (Figure 4) in which we simply put next to each other in evolution those genes encoding peptide chains with the fewest amino acid differences. We postulated that evolution occurred via gene duplication, itself not a new idea, followed by independent evolution of the resulting “daughter” genes (L ewis 2003). This evolution was not quite independent, however, since α-like and β-like genes could evolve only within the confines of the concept that they must remain able to form α2X2 tetramers. This was essential to preserve the cooperative interaction between subunits that allows the very advantageous sigmoid oxygenation curve. The scheme was well received and adapted to many other evolutionary situations.


Sickle Cell Anemia

blood cells to sickle. Additionally, the polymerization of the hemoglobin protein does not occur until red blood cells release oxygen molecules. When a red blood cell with the Hb S mutation is carrying oxygen, it reverts back to the typical red blood cell shape and depolymerizes. The protein therefore constantly switches between polymerization and depolymerization, which causes the membranes of red blood cells to become rigid. The abnormal shape of the red blood cells as well as the membranes' rigidity causes an obstruction in smaller sized blood vessels, damaging organs.




Implications:

Because of the red blood cell's abnormal shape during sickle-cell anaemia, each red blood cell dies after ten to twenty days after its genesis. In contrast, a normal red blood cell can survive in the body for approximately 120 days. As a result of the blood cell's extremely short life span, the bone marrow

(responsible for red blood cell production) cannot replace the dead blood cells fast enough. In addition, the blood cell's abnormal shape and rigidity prevents proper blood flow through capillaries, facilitating poor oxidation of organs and tissue. This, coupled with the gradual organ damage that sickle-cell anaemia causes makes for a very bleak prognosis for sickle-cell anaemia patients.

Most of sickle-cell anaemia's implications are non-lethal. In fact, the most well-known implication is referred to as the sickle cell crisis. This event is characterized by a long-lasting incidence of pain. The event most often occurs in regions of the body where accumulations of sickle-cells exist, specifically the lungs, bone, brain, liver, eyes, spleen, penis, and kidneys. A person experiencing a sickle cell crisis will feel extreme, localized pain in one of these regions for anywhere between 3-14 days.

There are also several other non-lethal implications associated with sickle-cell anaemia, including acute chest syndrome. Here, a patient will experience acute chest pain associated with coughing up blood. Impairment of the central nervous system and eye function are some other significant implications of sickle-cell anaemia.

A very thorough list of symptoms associated with sickle-cell anaemia can be found here: http://www.mayoclinic.com/health/sickle-cell-anemia/DS00324/DSECTION=symptoms

Treatment:

In almost every case, sickle-cell anaemia has no cure. However, on a very rare occasion blood and marrow stem cell transplants can act as a cure for the disease. The primary objective while treating a patient with sickle cell anaemia is to alleviate as much pain as possible during the patient's life. Treatments also often try to prevent some of the complications associated with the disease as well as prevent organ damage. Usual treatments to address crises and acute pain attacks caused by sickle-cell anaemia oxygen therapy as well as the use of powerful pain medications called opioids.

Particularly severe cases of sickle-cell anaemia are sometimes treated with a substance called hydroxyurea. This medication induced your body into created fetal hemoglobin, which can sometimes prevent red blood cells from sickling. However, this drug reduces the quantity of white blood cells found in the body and can therefore make patients with sickle-cell anaemia more vulnerable to infection.

Additionally, there are various treatments that aim to address the complications of sickle-cell anaemia. These will be addressed below in the complications section.

Complications:

The primary complications associated with sickle-cell anaemia include stroke, pulmonary hypertension, organ damage, blindness, skin ulcers, and gallstones. Patients with sickle-cell anaemia are more susceptible to strokes due to the sickle-shaped red blood cells blocking blood flow to the brain. Additionally, these cardiovascular blockages can also cause high blood pressure in the lungs, defined as pulmonary hypertension. This complication can potentially be fatal. Similar to the causes of other complications, a lack of oxygen-rich blood flow to the body's organs can damage tissues, organs, and nerves throughout the body, as well as damage to the retina of the eye, causing blindness. Lastly, the decomposition of red blood cells in the body releases bilirubin, which in high quantities can cause gallstones.


Treatment Treatment

The resources below provide information about treatment options for this condition. If you have questions about which treatment is right for you, talk to your healthcare professional.

Management Guidelines

  • Project OrphanAnesthesia is a project whose aim is to create peer-reviewed, readily accessible guidelines for patients with rare diseases and for the anesthesiologists caring for them. The project is a collaborative effort of the German Society of Anesthesiology and Intensive Care, Orphanet, the European Society of Pediatric Anesthesia, anesthetists and rare disease experts with the aim to contribute to patient safety.

FDA-Approved Treatments

  • Hydroxyurea(Brand name: Droxia) - Manufactured by Bristol-Myers Squibb Co
    FDA-approved indication: To reduce the frequency of painful crises and to reduce the need for blood transfusions in adult patients with sickle cell anemia with recurrent moderate to severe painful crises (generally at least 3 during the preceding 12 months).
    National Library of Medicine Drug Information Portal
    Medline Plus Health Information
  • L-glutamine oral powder (prescription grade)(Brand name: Endari) - Manufactured by Emmaus Medical, Inc.
    FDA-approved indication: To reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older.
    National Library of Medicine Drug Information Portal
  • Hydroxyurea(Brand name: Siklos) - Manufactured by Addmedica Laboratories
    FDA-approved indication: To reduce the frequency of painful crises and to reduce the need for blood transfusions in pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crisis.
    National Library of Medicine Drug Information Portal
    Medline Plus Health Information

Frequency

Sickle cell disease affects millions of people worldwide. It is most common among people whose ancestors come from Africa Mediterranean countries such as Greece, Turkey, and Italy the Arabian Peninsula India and Spanish-speaking regions in South America, Central America, and parts of the Caribbean.

Sickle cell disease is the most common inherited blood disorder in the United States, affecting an estimated 100,000 Americans. The disease is estimated to occur in 1 in 500 African Americans and 1 in 1,000 to 1,400 Hispanic Americans.


Sickle Cell Anemia* - Biology

A. The Unique Geographic Distribution Pattern of Sickle-Cell Anemia

Almost as soon as sickle cell anemia was recognized as a blood-based disease, its higher frequency in families of African descent was noted. However, the first reports of cases in Africa itself did not come until the 1920s. In 1925 a 10-year old Arab boy was admitted to a hospital in Omdurman in the Sudan (on the Upper Nile, East central Africa, near Ethiopia) with severe weakness later he was ascertained to have sickle cell disease (anemia). In 1944 R. Winston Evans, a pathologist at the West African Military Hospital, studied the blood of 600 men from Gambia, the Gold Coast, Nigeria and the Cameroons (all in western Africa on the Gulf of Guinea). He found about 20% of the population affected by the sickle-cell condition (disease + trait). However, a striking observation became apparent: while the frequency of sickle-cell trait in Africa was three times that in the United States, sickle cell disease was much less common. Even as late as the 1950s it was still unclear why this discrepancy existed. Three hypotheses existed at the time: (a) Adult Africans are healthier than those living in urban America and thus do not show the effects of the disease as readily (b) Infant mortality, especially for Hb S Hb S children, is much higher in Africa than in the U.S., so that homozygous recessive children never reach adulthood (c) By chance fewer homozygous recessive individuals are conceived in Africa than in the United States.

In-Text Question 6 : Which of these options do you think might explain the discrepancy?

In certain parts of Africa today, the frequency of the mutant gene for sickle-cell (Hb S ) is very high (5-20%) as shown in the distribution map below:

How can we account for this very high frequency of a gene for a condition that can leave up to 25% of the population severely debilitated (with sickle cell disease)? It is logical to think that natural selection would have eliminated the gene from the population, especially since selection against homozygous recessive individuals has been almost 100% in the past (i.e., those individuals never lived to reproductive age). That it has not done so (apparently) became a major question for both geneticists and medical epidemiologists by the 1950s. The matter was all the more puzzling since the frequency of the HbS gene in the United States is less than that in Africa: 0.05 in the U.S. compared to 0.1-0.2 in central west Africa, even those most U.S. blacks came from those very populations in central west Africa where sickle cell anemia is so prevalent.

B. The Malarial Connection

In 1946 E.A. Beet, an MD in Northern Rhodesia noted that of a population of patients in his hospital, 15.3% of those who had normal blood had malaria, while only 9.8% of those with sickle cell (trait or disease) had the disease. Anthony C. Allison, a British medical doctor who had also taken a degree in biochemistry and genetics at Oxford shortly after World War II, studied the African situation closely in the early 1950s and published an important paper in 1954 outlining his hypothesis for why the African frequencies of the Hb S gene were so high (he had found that in some tribes up to 40% of the individuals were heterozygous for sickle-cell trait). He reasoned that if natural selection were working to eliminate the recessive mutant gene, it would be necessary to invoke a mutation rate (from Hb A to Hb S ) 1000 times higher than known for any other human gene in order to explain the continued high frequencies of HbS in the popluation. This seemed so unlikely he reasoned that some other forces must be at work.

Allison thought it was significant that the frequency distribution of the sickle-cell condition mapped out very closely to the distribution map for the most severe forms of malaria, those caused by the protozoan Plasmodium falciparum , as shown in the map below:

Borrowing the concept of balanced polymorphism from his teacher E.B. Ford at Oxford, Allison hypothesized that children in these regions who are heterozygous for HbS (i.e., HbAHbS) have an advantage in combatting the effects of malaria over individuals with normal hemoglobin (i.e., HbAHbA). Homozygous recessive individuals (HbSHbS) may also have an advantage against malaria, but they have all the other problems associated with sickle cell disease, and hence are severely selected against and seldom reproduce.The situation in which the heterozygote in any population is selectively favored over either homozygote is what is known as balanced polymorphism . It works to maintain a high frequency of the recessive mutant gene even though that gene is highly deleterious in the homozygous recessive form. At the time Allison did not know how the presence of sickle-cell hemoglobin conferred selective protection against malaria, but the connection seemed clear to him. In a non-malarial environment such as the United States, the heterozygotes would not have a selective advantage, and hence both hetero- and homo-zygote recessives would be selected against. Thus, in accordance with the data, sickle-cell was lower in frequency in the U.S. because there was no advantage to the heterozygote or the homozygote recessive.

An American geneticist, James V. Neel, also studied sickle cell frequencies and concluded that in malarial environments, heterozygotes (with sickle-cell trait) have an increased fitness (chance of leaving offspring) of 15% over those with normal hemoglobin.

C. How Does Sickle-Cell Help Combat Malaria?

There are at least three other Plasmodium species that produce milder forms of malaria. P. falciparum infection remains one of the major causes of human deaths in the world today.

While reproducing asexually inside the red blood cells, the merozoites have a high metabolic rate, and consequently consume lots of oxygen. If the individual is heterozygous for sickle-cell trait, half their hemoglobin is Hb A Hb S , and thus will sickle when the oxygen tension becomes very low inside the red blood cells (recall that sickling does occur in heterozygous individuals, only at a lower oxygen tension than for homozygotes). These sickled cells are removed from the body by the spleen, along with the merozoites inside of them . Thus heterozygotes on the average remove merozoites from their body before the microorganisms have a chance to produce a large infectious population inside the body. It is this sleective advantage of the heterozyote that maintains the Hb S gene at a higher level in malarial than in non-malarial environments.


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