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Sickle Cell Disease

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Title: Sickle Cell Disease


1
Sickle Cell Disease
  • By Cecil, Caitlin, and Kerri
  •  

2
What is Sickle Cell?
  • People who have Sickle Cell have sickle shaped
    red blood cells, which causes complications
    because the blood cells are not able to reach
    certain parts of the body.

3
Red blood cells Going through Vessels
4
Symptoms of Sickle Cell
  • Abdominal and bone/joint pain
  • Breathlessness
  • Delayed growth and puberty
  • Fatigue and fever
  • Jaundice (yellowed skin)
  • Paleness
  • Rapid heart rate
  • Greater risk for infection
  • Adolescents and adults can develop ulcers on
    their legs
  • Chest pain
  • Excessive thirst
  • Poor eyesight, blindness when blood cant get
    to the back of eyes, they dont have a constant
    nourishment, causing people to not be able to see

About 30 of Jamaican patients with Sickle Cell
develop ulcers in comparison to 1 of Americans
5
Diseases and Conditions people with Sickle Cell
are likely to develop
  • Acute chest syndrome
  • Aplastic crisis
  • Dactylitis swelling of the hands and feet
  • Painful crises really painful episodes when
    blood cells are blocked from going to certain
    parts of the body pain can occur anywhere, but
    it is usually in the chest, arms, and legs
  • Enlarged spleen sickle cells pool in the
    spleen, and in some cases there is no spleen in
    the body.
  • Stroke
  • Hematuria

An enlarged and unhealthy spleen from someone
with Sickle Cell
An x-ray of a hand swollen from dactylitis
6
The History of Sickle Cell
  • Many people of African tribes were the first to
    develop sickle cell disease
  • Most of the names they had for it had multiple
    syllables maybe to account for the many painful
    episodes
  • The tribes thought that there were evil spirits
    and the babies that died from sickle cell were
    sacrificing their lives for the family

7
More History…
  • 1846 In the US, a scientist wrote a paper called
    Case of Absence of the Spleen, which talked
    about a runaway slave whose body was autopsied
    and they found he did not have a spleen.
  • 1904 A hospital intern discovered the sickle
    shaped cells in a patient at a hospital.
  • 1910 The first formal report came out that gave
    details about the strange disease
  • 1922 The disease was finally named Sickle Cell

8
Who would you think has Sickle Cell?
Hispanic boy
Indian girl
White girl
Black boy
9
Sickle Cell Anemia It's Not a Black
Disease
  • One of the common misconceptions is that only
    black people get sickle cell, but this is not the
    case.
  • There are many different ethnicities that can
    have sickle cell.

10
Who can get Sickle Cell?
  • ANYONE can get Sickle
    Cell Disease.
  • It is most common in the following ancestries
  • African
  • Central or South American
  • Cuban
  • Indian
  • Saudi Arabian
  • Mediterranean
  • Hispanics

11
Prevalence
  • It is estimated the up to 80,000 people in
    America have Sickle Cell Disease
  • 1/500 African Americans have Sickle Cell Disease
  • 1/1000 -4000 Hispanics have Sickle Cell
  • 1/12 African Americans are carriers for Sickle
    Cell
  • 1/50 Asians are carriers for Sickle Cell
  • 1/100 Greeks are carriers for Sickle Cell

12
Diary of a Man with Sickle Cell
  • In the mid 60's, my family moved to the
    suburbs. For a black family in those days, that
    was a big thing. We moved into a three bedroom
    house complete with a bath and a half, and a
    pool! Yeah, we were living large. The summer that
    we moved, my brother, sister and I were ecstatic 
    over having a pool. As soon as the weather
    permitted, we jumped into our swimming suits and
    bounded for the cement pond …About a week or two
    after we started all this frolicking in the
    water, I became very ill. Confined to my bed, I
    writhed in pain, suffering one of my worst crisis
    ever. Like always, I basically had to brave the
    pain out sans pain medicine. My parents were
    convinced that the day they gave me even the
    mildest aspirin would be the day I'd become a
    junky. Exhausted and weak, I finally recovered.
  •   Not long after that, I rejoined my brother and
    sister in our never-ending party around the
    pool…After another day or so of exposure to the
    cold water, I took ill again. This one wasn't as
    bad and my mother just figured this was what
    having a sickly child meant.

13
  •  
  • It wasn't until about the third time I got sick
    that my parents began to get concerned. "Why does
    this boy keep getting sick?" my father inquired.
    He usually held my mother accountable for our
    condition and when I got sick, he demanded an
    explanation. When my mom couldn't supply one, my
    dad decreed that I was to go see the doctor.
  • The doctor was as clueless as my parents,
    however. Sickle Cell was a disease that doctors
    knew little about in those days, and each doctor
    practically formed his own protocol. The doctor
    started asking if my routine had changed.
  • "Has he had any colds of flu lately?" My mom
    answered no.
  • "Has he been doing something different? Less
    rest, or anything?" My mom thought for a little
    while and then finally she offered,
  • "Well he's been playing in the pool a lot."
  • "The pool!" The doctor was startled. He
    explained to my mother that there were certain
    things a child with Sickle Cell should avoid,
    number one of them being extreme cold
    temperatures. He immediately wanted to know if
    the pool was heated and when he found out it
    wasn't he instructed my mother to limit my time
    in the pool.
  • I was sorely disappointed once I understood the
    full implications of this new ruling. While I
    didn't want to experience another of those
    excruciatingly painful crisis, it felt like
    someone had dealt me a bad hand when I watched my
    sister play in the water all day. I would dabble
    in the water and then get out as soon as I felt
    myself getting a little cold.  
  • Although it never was the same for me with the
    pool, I eventually learned a balance that allowed
    me to enjoy as much fun possible. In turn, I'd
    sit on the side of the pool and vicariously enjoy
    the fun my siblings had until it was safe for me
    to go back in. Even to this day, I rarely spend
    more than 30 minutes at a time in a pool. It was
    a hard lessen, learned by too many times
    suffering, but it came along with the territory
    for a kid living with Sickle Cell.

14
Sickle cell and malaria
Distribution of the sickle cell allele
Distribution of Malaria
As you can see, the areas where Malaria is
present and the Sickle Cell allele is present are
overlapping.
15
It is Unknown why people with the Sickle Cell
Trait are resistant to Malaria, but there are
several theories…
  • The carriers of Sickle Cell have some abnormal
    Hemoglobin, and when they come in contact with
    the Malaria parasite they become sickled. Then
    those cells go through the spleen, which
    eliminates the cells because of their sickle
    shape, so the Malaria would be eliminated as
    well.
  • The Sickle Cell trait causes the malaria to stay
    in the body for an extended period of time, so it
    is able to build up a defense to it.
  • Because oxygen concentration is low in the
    spleen, and because infected
  • cells often get trapped in the spleen, it is
    possible that they are destroyed in the spleen
  • 4. The Malaria parasite produces an acid when it
    is inside of the red blood cells. This causes
    the red blood cells to polymerize, and the cells
    will sickle. These sickled cells are then
    destroyed when the blood cells go through the
    spleen.

16
An Experiment on Sickle Cell and Malaria in 2005
  • There were over 1000 people chosen from Kenya,
    which is a place where Malaria is very prominent
  • The doctor performing the study, Dr. Tom
    Williams, found that the protection to Malaria
    from having the Sickle Cell trait rose from 20
    in the first two years of life to 50 and over by
    the age of 10.
  • His theory of the resistance of people with
    sickle cell trait results from the immune system
    building a defense.

17
Prognosis
  • People can live a relatively normal life with
    Sickle Cell if they have the proper treatment.
  • The average life expectancy for males is 42.
  • The average life expectancy for females is 48.
  • In 2003 the oldest patient to have Sickle cell
    was an 85 year old Jamaican woman.

18
Genetics of Sickle Cell
  • Sickle cell is an autosomal recessive disease.
  • Therefore, the child can only get Sickle cell if
    both parents are carriers, not if only one is and
    the other is normal. They have a 25 chance of
    getting it if both are carriers

19
The Proteins of Hemoglobin A
  • There are 4 protein subunits of Hemoglobin A
  • There will be different forms of Hemoglobin when
    there is a mutation in the beta subunit.

20
A carrier for Sickle Cell Will have…
  • An S mutation in one copy of the hemoglobin beta
    gene.
  • Half of the beta subunits are replaced with Beta
    S.
  • This person has the Sickle Cell trait.

21
  • When a person is a carrier, they will have
  • 25 normal HbA 50 HbS
  • 25 HbSS

22
Sickle Cell Disease HbSS
  • This results when both copies of the hemoglobin
    beta gene have an S mutation.
  • All of this persons beta subunits are replaced
    by beta S.

23
Hemoglobin C
  • This results when one of the beta subunits is
    replaced with beta C and one is replaced with
    beta S.
  • If a person has Hemoglobin C, they have sickle
    cell hemoglobin C.

The mutation that causes this change in the beta
happens because a glutamic acid residue replaces
a lysine residue at the sixth position of the
beta globin chain.
24
Hemoglobin Gene
  • The gene related to sickle cell anemia is the
    hemoglobin gene (HBB).
  • Hemoglobin contains iron and transports oxygen
    from the lungs to the peripheral tissues.
  • The HBB protein is 146 amino acids long.
  • The HBB gene is found on chromosome 11.

25
Location of the HBB Gene Chromosome 11
Chromosome Map From http//www.ncbi.nlm.nih.gov/m
apview/maps.cgi?ORGhumCHR11MAPSideogr5B11pte
r3A11qter5D,loc5B0.0000003A142127415.0000005D
queryeHBB
26
HBB Gene Continued…
  • Most people receive two normal hemoglobin genes
    (one from the mother and another from the
    father).
  • Carriers, or people exhibiting the sickle-cell
    trait have only one normal hemoglobin gene.
    Carriers rarely exhibit symptoms and are almost
    always completely normal.
  • People that have Sickle-Cell Disease have two
    abnormal hemoglobin genes.

27
HBB Gene Hb S Variant
  • Sickle cell is most commonly caused by the Hb S
    variant
  • Valine, a hydrophobic amino acid replaces
    glutamic, a hydrophilic amino acid at the sixth
    amino acid position in the HBB polypeptide chain.
  • This causes the new hydrophobic spot on the
    outside of the protein to be attracted to the
    hydrophobic spot on the hemoglobins beta chain.
    Subsequently, the cell experiences a loss of
    plasticity due to change in surface tension as
    the Hb S molecules clump together, causing the
    sickling of the cells.

28
Who is Tested?
  • Screening test is often performed when one is a
    newborn or a young child.
  • As the disease is more prominent with African
    ancestry, many people of this descent choose to
    be tested before having children (as one can be a
    carrier).
  • Prenatal testing can also be performed with
    amniocentesis and Chorionic Villus Sampling.
    However, one must request testing for sickle cell
    anemia when these procedures are done if they are
    of increased risk (such as family history).
  • People of African or Caribbean descent should be
    tested before anesthesia.

29
Testing
  • How is sickle cell disease diagnosed?
  • Many states now use hemoglobinopathy testing
    (looking at the blood for abnormalities of
    testing) as part of the newborn screening blood
    tests between 2 and 7 days of age.
  • Careful examination of family history.
  • Physical examination some symptoms are visible,
    such as jaundice.
  • A hemoglobin electrophoresis can determine if a
    person is a carrier.

30
The Blood Test
  • A chemical that reduces the amount of oxygen the
    blood carries is added to the patients blood.
  • If the patient carries the sickle cell gene, then
    the lowered oxygen level will cause crystals to
    form.
  • These crystals alter the shape of the red blood
    cell, giving it the sickle shape
  • The different types of hemoglobin are separated,
    so the number of hemoglobin S can be identified
    and a diagnosis can be made.

31
The Results…
  • In people without the trait, no Hb S is present.
  • In carriers, Hb S constitutes 20 to 40 of the
    hemoglobin many carriers never exhibit
    symptoms, although they may be present to a small
    degree.
  • In people with the disease, 80 to 100 of the
    hemoglobin may be Hb S

32
Tests may not be accurate if…
  • You have had a blood transfusion within the past
    four months.
  • You have polycythaemia (increased red blood cell
    production).
  • If you are on certain medications talk to your
    doctor!

33
Ethical Issues
  • Testing for sickle cell is not very controversial
    aside from the controversy associated with
    genetic testing in general.
  • Pre-natal screening and terminations of pregnancy
  • Playing God
  • Discrimination in the workplace

34
Oliver Smithies
  • He is exploring the possibility of gene targeting
    as a possible cure for sickle cell anemia and
    beta-globin thalassemia (thalassemia is when
    normal hemoglobin protein is produced in smaller
    quantities).
  • Gene targeting uses homologous recombination
    DNA is broken and then joined to the end of a
    different DNA molecule between exogenous DNA
    and a specific chromosomal gene.
  • Right now, they are attempting to correct a
    specific type of beta-globin thalassemia which is
    caused by a deletion.
  • They are injecting mice stem cells, corrected
    genes are identified using a specific protocol
    designed especially for the corrected gene, and
    the corrected genes are then observed.
  • They are planning to carry out similar
    experiments with the sickle cell beta-globin gene.

35
Oliver Smithies Continued…
  • Smithies and his team are also able to duplicate
    the embryonic stem cells from mice and then
    restore or demolish the specific function of a
    gene. The modified cells are then reintroduced
    into a normal blastocysts, and the animals then
    exhibit the modified genes. In some cases, they
    have even been able to transmit the modified gene
    to the animals offspring.
  • They are hoping to use this method in order to
    make animal models of sickle cell anemia.

36
Oliver Smithies Continued…
Chromosome 11
HBB Gene Enlarged Shows Hb S variant
STEP 1 Wildcard gene is inserted
STEP 2 homologous recombination occurs
As the two genes are similar, the part of the
normal HBB gene between the two Xs is able to
take the place of the part of the gene between
the two Xs of the gene exhibiting the Hb S
variant
THE RESULT
37
Philippe Leboulch Attempts to Cure Sickle-Cell
through Gene Therapy (2001)
  • Known (from earlier studies) that the protein
    gamma globin stops polymerization (the sticking
    together of hemoglobin). If a gamma globin gene
    is added to a beta globin gene, then the
    hemoglobin can resist polymerization.
  • Bone marrow was taken from mice infected with
    sickle-cell, and the modified gene was added to
    it.
  • But did this prevent the sickling of cells?
  • The modified marrow was injected into healthy
    mice (whose marrow had been taken out) to see if
    they developed sickle-cell.
  • These mice didnt get sick, however, those
    injected with non-treated marrow did.
  • How did they do it?
  • The beta globin gene was delivered to the marrow
    by putting it with a gene usually found in HIV.
    Other DNA was also added to assist with the
    production of the beta globin.
  • After 10 months, all treated mice were making
    their own beta globin as a result of the altered
    gene, and therefore, there were few sickling
    cells.
  • The Problem?
  • Who wants to use genes associated with HIV?
  • Destroying all bone marrow is dangerous.

38
Philippe Leboulch Continued…
http//www.sciencenews.org/articles/20011215/fob1.
asp
39
Treatment Options For Sickle Cell Anemia
40
Main Treatment Methods
  • There is no known cure for sickle cell anemia.
  • The four main treatment options are
  • Blood Transfusions
  • Drug Treatment
  • Blood and Marrow Stem Cell Transplantation
  • Gene Therapy
  • These main treatment options for the painful
    crisis involves heavy reliance on painkilling
    drugs and oral and intravenous fluids whose main
    functions are to reduce pain and prevent
    complications.

41
Blood Transfusions
  • Definition
  • Blood transfusion involves transferring healthy
    blood from one person into the circulatory system
    of another person.
  • Blood transfusions are mostly known for their
    life-saving use in situations involving massive
    blood loss due to trauma, however its use in
    treatment of sickle cell anemia is increasing.

42
Blood Transfusion
  • What does it do?
  • In sickle cell anemia red blood cells become
    sickle shaped.
  • Painful crises as tissues become depleted of
    oxygen
  • Useless red blood cells build up in blood vessels
    leading to stroke.
  • Blood transfusions reduces this pain by
    increasing the number of functioning red blood
    cells in the body and hence increasing the oxygen
    carrying capacity of the blood. These
    transfusions can also improve conditions such as
    an enlarged spleen and strokes, which sickle cell
    patients are especially at risk for.

43
Blood Transfusions
  • Effectiveness
  • Blood transfusion is currently the single most
    effective and proven treatment for severe
    complications of sickle cell disease. It also
    significantly reduces strokes.
  • Age
  • Blood transfusions are mostly administered to
    children who have severe cases of sickle cell
    anemia. However, persons of all age can receive
    this treatment.
  • Cost
  • The cost for one blood transfusion is around
    450, and they should be administered once a
    month in children for its positive effects to be
    really seen.

44
Drug Treatment
  • Persons with sickle cell anemia are especially
    susceptible to infection.
  • The two main drugs used in treatment of sickle
    cell anemia are penicillin and hydroxyurea.

45
Drug Treatment
  • Penicillin
  • Persons with sickle cell anemia have an increased
    susceptibility to infection due to damage to one
    of our major defenses against infection, the
    spleen, due to restricted blood flow.
  • Penicillin is an antibiotic which would attack
    these infections helping in quick healing and
    protection.
  • Folic acid, which aids in the formation of
    healthy blood cells could also be taken daily in
    large quantities as well.

46
Drug Treatment
  • Penicillin
  • Cost
  • 54.90 for 30 Tablets
  • Penicillin should be taken once a day everyday so
    that effective protection against possible
    infection could happen.

47
Drug Treatment
  • Hydroxyurea
  • Hydroxyurea was the first effective drug
    treatment for adults with severe sickle cell
    anemia.
  • A study showed that daily doses of the
    anticancer drug hydroxyurea reduced the frequency
    of painful crises and acute chest syndrome in
    sickle cell anemia. In addition, patients taking
    the drug needed fewer blood transfusions.

48
Drug Treatment
  • Hydroxyurea
  • How does it work?
  • Higher doses results in large increases in
    fetal hemoglobin concentrations as little as a
    four percent increase in HbF concentrations was
    needed to help prevent some sickling of cells.
  • Hence, if less cells are sickled the symptoms
    of the disease are reduced.
  • Cost
  • Hydroxyurea costs around 90 for 100 capsules.

49
Blood and Marrow Stem Cell Transplantation
  • Bone marrow transplants are the closest
    things possible to a cure for sickle cell anemia.
  • Process
  • In bone marrow transplantation, the affected
    persons bone marrow is replaced with cells
    containing genes for the non-sickle cell
    hemoglobin.
  • Production of healthy red blood cells starts and
    the sickle shaped cells are prevented. If the
    transplant is performed when the affected person
    is still young then success rates can be as high
    as 90-95.(Sickle Cell Society 2005)

50
Bone Marrow and Stem Cell Transplantation
  • Problem
  • An obstacle with this kind of treatment
    finding enough donors for such an invasive and
    painful procedure, as well as finding specific
    donor/patient matches.
  • Cost
  • Bone Marrow transplantation can cost as much
    as 30000 and so only certain people could
    afford this form of treatment.

51
Gene Therapy
  • Definition
  • Gene therapy is the relatively new idea of
    inserting genes into the cells of an individuals
    tissues and cells in order to treat a hereditary
    disease, such as sickle cell anemia, in which a
    defective mutant allele is replaced with a
    functional one.
  • Gene Therapy would be the best cure for sickle
    cell anemia, but work in this method of treatment
    is still very new.

52
Gene Therapy
  • What It Involves
  • Two methods of gene therapy are being explored.
  • Correction of Gene
  • Turning Off Gene
  • Correction of Gene
  • Scientists are looking at whether
    correcting the defective gene in sickle cell
    anemia and inserting it into the bone marrow of
    people with sickle cell anemia will result in the
    production of normal adult hemoglobin.
  • Turning Off Gene
  • Some other scientists are looking at the
    possibility of turning off the defective gene and
    simultaneously reactivating another gene that
    turns on the production of fetal hemoglobin.

53
Gene Therapy
  • Cost
  • The cost of gene therapy is very high at this
    point in time. However, Gene therapy will
    probably be cheaper in the long run since it is a
    one time only procedure. It will eliminate
    suffering for the individual and possibly their
    children.

54
Video Newscast- Treatment of sickle cell
  • http//video.google.com/videoplay?docid4164829552
    325284094qsicklecellanemiatreatmenttotal19
    start0num10so1typesearchplindex0

55
Works Cited
  • "Carolina The curriculum in genetics and
    molecular biology." Oliver Smithies, D Phil.
    2007. 30 Oct 2007 lthttp//gmb.unc.edu/faculty/smi
    thies.htmgt.
  • "HBB The Gene Associated with Sickle Cell
    Anemia." Human Genome Project Information. 16 Oct
    2007 lthttp//www.ornl.gov/sci/techresources/Human
    _Genome/posters/chromosome/hbb.shtmlgt.
  • Seppa, Nathan . "Gene Therapy for Sickle-Cell
    Disease?." Science News 160.2415 Dec 2001 372. 1
    Nov 2007 lthttp//www.sciencenews.org/articles/200
    11215/fob1.aspgt.
  • "Sickle Cell Anemia." Diseases and Conditions
    Index. National Heart Lung and Blood Institute.
    30 Oct 2007 lthttp//www.nhlbi.nih.gov/health/dci/
    Diseases/Sca/SCA_Causes.htmlgt.
  • "Sickle Cell Anemia." Human Diseases and
    Conditions. 2007. 30 Oct 2007 lthttp//www.humanil
    lnesses.com/original/Se-Sy/Sickle-cell-Anemia.html
    gt.
  • "Sickle Cell Disease." Health Information.
    Children's Hospital of Wisconsin. 16 Oct 2007
    lthttp//www.chw.org/display/PPF/DocID/21860/route
    r.aspgt.
  • "The Test." Sickle Cell Test. Lab Tests Online.
    16 Oct 2007 lthttp//www.labtestsonline.org.uk/und
    erstanding/analytes/sickle/test.htmlgt.
  • "What is Sickle Cell Anaemia?." Sickle Cell
    Society. Sickle Cell Society. 27 Sep 2007
    lthttp//www.sicklecellsociety.org/education/sickl
    ecell.htmanchor62960gt.
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