Download Down syndrome

Baby Doe v. The Prenatal Clinic
Norris Armstrong
University of Georgia-Athens
1
Baby Doe v. The Prenatal Clinic
John looked at the baby squirming in his arms. He and his wife,
Jane, had been trying to have kids for a couple of years and had
finally been successful. The pregnancy was uneventful and, though
the delivery took longer they either of them would have liked,
everyone seemed to be doing fine.
This was a new experience for John. Everything about the child he
was holding seemed so small and delicate. Even so, some things
seemed unusual. For example, the baby looked a little cross-eyed,
and its face seemed a little flat when he looked the baby from the
side. Also, the baby’s hands and feet were even smaller than he
would have expected, and the hands had a strong crease that ran
across the middle of the palms. John realized he was probably
imagining things. After all, though he had a younger brother, he
was definitely no expert on newborn babies.
2
One week later…
But one week later John and Jane sat in the clinic’s conference
room in stunned silence. “I had to run some tests to be certain,”
said their doctor. “However, the results confirmed what I
suspected. Your child has Down syndrome. I am afraid there is no
cure. However, early intervention can improve the outcome you
can expect. I can give you the names and numbers for several
organizations that can give you
well
more information and
advice. There are
other resources
you can try as
………………”
John and Jane did not hear much of what the doctor said after the
diagnosis. The only thought that kept running through their minds
was, “How could this have happened?”
3
The Case
You’ve been hired by a law firm to serve as an expert witness for
John and Jane’s case. To help your client and to appropriately
inform the court, you will need to explain what actually causes
Down syndrome to the jury. You will also need to explain whether
or not the clinic could have done anything that contributed to the
baby’s condition.
Since it was likely to have been many years since most of the jurors
had studied biology, one of the things you probably have to do is
give them a crash course on some basic biology.
For starters, what exactly is Down syndrome?
4
CQ#1: What is Down syndrome?
A. A condition caused when the mother drinks
alcohol while pregnant.
B. A form of childhood cancer.
C. A birth defect resulting in a split upper lip and
speech problems.
D. A condition caused when the baby has too many
copies of a chromosome.
E. A form of brain damage that results when the baby
receives too little oxygen during birth.
5
Down syndrome
• A chromosomal disorder resulting from a partial or complete extra
copy of chromosome 21.
• Multiple developmental and health effects including:
• Short stature, distinct facial features.
• Mild to moderate physical and cognitive impairment.
• Increased risk of problems involving heart, respiratory, digestive,
hearing, vision, and/or thyroid glands.
• Trisomy 21 (95% of all cases): three complete copies in all cells.
• Mosaicism (1-2% of cases): three copies in some but not all cells.
• Translocation (3-4% of cases): partial copy of chromosome 21
attached to another chromosome.
6
What are chromosomes?
7
What are chromosomes?
•Human cell = >6 billion nucleotide base pairs (~2 meters)
•Wrapped around protein = chromatin
•DNA/protein = chromosome
8
How many chromosomes do humans have?
• Humans are diploid (2n)
• Two of each chromosome, one from each parent.
• n = 23 unique chromosomes (haploid #) Curly hair
allele
• 2(n) = 46 total chromosomes
Strait hair
allele
• The two copies of each chromosome in
human cells are homologous
• Different versions - same genes in same
locations but different DNA sequence.
• Different versions (alleles) of a gene may
promote different traits (e.g. hair type).
9
CQ#2: The diploid chromosome
number in standard laboratory
mice (genus Mus) is 40.
What is n for this organism?
10
Getting Ready
The first court date for John and Jane’s case is coming up
and it is time to start organizing your testimony. You
need to help the jury determine whether the doctors at the
clinic may have done something to cause the baby to
have the incorrect number of chromosomes.
A good place to start might be to describe how cells get
the right number of chromosomes in the first place.
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How do cells get
the right number
of chromosomes?
DNA
DNA
DNA
DNA
DNA
DNA
DNA
Cell Division
1. Duplicate cell components
• Organelles
• Cytoplasm
• Chromosomes
2. Separate the material into
two daughter cells
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Cell Cycle
•Interphase
•Cell division
M
G2
S
G1
13
DNA Packaging
14
Interphase
Mitosis
•Prophase
•Metaphase
•Anaphase
•Telophase
15
CQ#3: If you investigated cells from
a lab mouse with 40 chromosomes
you would find a total of __ sister
chromatids first after the ___ stage.
A.
B.
C.
D.
10: G1
20: G2
40: M
80: S
16
Insert photos of celebrity
families here
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Families: similar yet different. Why?
Asexual Reproduction
•Single parent
•Offspring identical to each other and parent
Sexual Reproduction
•Two parents
•Offspring are unique
•Offspring are similar to each other and parents
•Combine DNA from two individuals
•Combines characteristics of both individuals
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Why do diploid organisms need
to have specialized sex cells?
• Sex cells (gametes: sperm or egg) allow traits
to be combined from two organisms
2n
(46)
+
2n
(46)
4n = 92
too many
19
Sexual Reproduction
• Gametes have only one of each chromosome
• Requires special cell division: Meiosis
•Diploid cells (2n)
Gametes (n)
•Takes place in gonads (testis, ovary)
n (23)
+
n (23)
2n = 46
20
How is Meiosis different from Mitosis?
Mitosis
Cells divide 1x
Meiosis
Cells divide 2x
2n
2n
2n
2n
n
n
Diploid Cells
n n n n
Haploid Cells
21
Mitosis
Identical cells
Meiosis
Different cells
22
Mitosis
Cell division is
over
Meiosis
Cells divide again;
sister chromatids line up
Done
23
How many unique gametes can a cell with
two pairs of chromosomes make?
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Why bother?
•For humans with 23 pairs of chromosomes?
•(2)23
> 8 million different possible gametes
•For a couple
•possible unique offspring
•(8 million) x (8 million) = (64,000,000,000,000)
But wait! There’s more!
25
Crossing over enables even greater variety
• Exchange of equivalent sections between homologous
chromosomes.
• Occurs at random locations along chromosome.
• Creates new versions of chromosomes.
26
CQ#4: The cell to the right shows a diploid organism
with two chromosomes (2n=2). The pictures below
show some of the steps this cell may go through
during mitosis or meiosis.
A.
D.
B.
E.
F.
C.
G.
H.
Place the appropriate steps in order for a cell going through
mitosis. (Note: you may use just some or all of the steps.)
27
CQ#5: The cell to the right shows a diploid organism
with two chromosomes (2n=2). The pictures below
show some of the steps this cell may go through
during mitosis or meiosis.
A.
D.
B.
E.
F.
C.
G.
H.
Place the appropriate steps in order for a cell going through
meiosis. (Note: you may use just some or all of the steps.)
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Parent #2
Parent #1
CQ#6: The different
copies of chromosome
21 in John and Jane are
shown to the right.
Which of the following is a normal gamete that
might be produced by either John or Jane?
A
B
C
D
E
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What went wrong?
Now that you’ve explained to the jury how cells normally
receive the correct number of chromosomes, you need to
explain whether this did not happen with John and Jane’s
baby because of something the clinic doctor’s may have
done.
What can cause a cell to inherit the incorrect number of
chromosomes?
30
CQ#7: How can a cell end up with an
incorrect number of chromosomes?
A. The chromosomes do not separate correctly
during mitosis or meiosis.
B. The chromosomes are copied incorrectly during
mitosis or meiosis.
C. Cells divide too many times.
D. The chromosomes become damaged when they
are being copied.
E. Cells eliminate chromosomes they don’t need.
Sometimes this doesn’t happen.
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Normal Meiosis
Non-Disjunction
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Parent #1
Parent #2
Down syndrome
The different copies of
chromosome 21 for John,
Jane, and their baby are
shown here.
Child
33
CQ#8:The different
copies of chromosome
21 for John, Jane, and
their baby are shown
here.
Parent #1
Parent #2
When and where did the
mistake occur?
A.
B.
C.
D.
E.
Meiosis I of parent #1
Meiosis I of parent #2
Meiosis II of parent #1
Meiosis II of parent #2
Either Meiosis I or II of parent #1
Child
34
What’s wrong with having 3 copies of a
chromosome?
• Three copies of a chromosome means three
alleles for each gene.
• Genes contain DNA
• DNA is the instructions for making proteins
35
Protein Synthesis
• Gene – DNA segment that carries a
blueprint for building one protein
• Proteins have many functions
– Building materials for cells
– Act as enzymes (biological catalysts)
• RNA is essential for protein synthesis
Role of RNA
• Transfer RNA (tRNA)
– Transfers appropriate amino acids to the
ribosome for building the protein
• Ribosomal RNA (rRNA)
– Helps form the ribosomes where proteins are
built
• Messenger RNA
– Carries the instructions for building a protein
from the nucleus to the ribosome
Transcription and Translation
• Transcription
– Transfer of information from DNA’s base
sequence to the complimentary base sequence
of mRNA
• Translation
– Base sequence of nucleic acid is translated to an
amino acid sequence
– Amino acids are the building blocks of proteins
Protein Synthesis
Figure 3.16
Figure 17.4 The dictionary of the genetic code
Figure 17.7 The initiation of transcription at a eukaryotic promoter
Transcription factors
control the expression
of a gene.
They must be present
for a gene to be on.
Figure 17.9 RNA processing: RNA splicing
Figure 17.17 The initiation of translation
Figure 17.18 The elongation cycle of translation
Figure 17.19 The termination of translation
So why is having three copies of a gene so bad?
• Since genes direct the construction of proteins,
having an extra one means 50% more protein is
made.
• Many genes on chromosome 21 code for
transcription factors. Making extra transcription
factors means many genes will be
“overexpressed”.
• Why this causes Down’s Syndrome is unkown.
46
47
Human Down Syndrome Cell Adhesion Molecule Gene
TATTATAATATAATTATTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTAC tata/promoter/start
TGACTGAGGCCGGAGCACGGCAAAGATGAGCCTGCCCGCCCGCCTGCTGCCTGGATGCGGAGGGTGAGGG
CTGGCGCACGGGAGGCCGCTGGCTGCGCATTCTGGGCGCCGAGTGCCCGGGATGAGCTCACGCCCGCGTC
TGCGGCTCTCTCCACCTGCCGACCTGCCGGGGGCCCACTGAGCTGACGGCGCACCTGGGCTCCGGCCGCA
GCGTGGGGCGCGGCGCCCGGGAGCAGGTGTGCAGGAGCGCAGCGCGCGGCGAGCGCAGCCCTCGCTCCGG
AGCCCGGCCGCGCCGCGTGCCCGGGCGGCTAGGCAGCGGCGGCGGCGGCGGCGGGCGGCGGGCGGGCGGC Intron??
GGCCCCCGGGCAGGTGCCGAGCGGCGAGCGGAGCCGGGCCGGGCGGAGCGCGGGGGGCGAGGCCGGCGCG
TCGCTCGCGGGAGGCCGGGGAGCGGCAGGGGCATGTGGATACTGGCTCTCTCCTTGTTCCAGAGCTTCGC
GAATGTTTTCAGTGAAGACCTACACTCCAGCCTCTACTTTGTCAATGCATCTCTGCAAGAGGTAGTGTTT
GCCAGCACCACGGGGACTCTGGTGCCCTGCCCCGCAGCAGGCATCCCTCCTGTGACTCTCAGATGGTACC
TAGCCACGGGCGAGGAGATCTACGATGTCCCCGGGATCCGCCACGTCCACCCCAACGGCACTCTCCAAAT
TTTCCCCTTCCCTCCTTCAAGCTTCAGTACCTTAATCCATGATAATACTTATTATTGCACAGCTGAAAAT
CCTTCAGGGAAAATTAGAAGTCAGGATGTCCACATCAAGGCTGTTTTACGGGAGCCCTATACAGTCCGTG
TGGAGGACCAGAAAACCATGAGAGGCAATGTTGCGGTCTTCAAGTGCATTATCCCCTCCTCGGTGGAGGC
GTACATCACTGTCGTCTCATGGGAGAAAGACACTGTTTCACTTGTCTCAGGATCTAGATTTCTCATCACA
TCCACGGGAGCCTTGTATATTAAAGATGTACAGAATGAAGATGGATTGTATAACTACCGCTGCATCACGC
GGCATCGATACACCGGAGAGACGAGGCAGAGCAACAGCGCCAGACTTTTTGTATCAGACCCAGCGAACTC
AGCCCCATCCATACTGGATGGGTTTGACCATCGCAAAGCCATGGCTGGGCAGCGTGTGGAGCTGCCTTGC
CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC intron (fiction)
AAAGCGCTCGGGCACCCTGAGCCAGATTACCGCTGGCTGAAGGACAACATGCCCCTGGAACTTTCAGGGA
GGTTCCAGAAGACCGTGACGGGGCTGCTCATTGAGAACATTCGCCCCTCGGACTCAGGCAGCTATGTTTG
TGAAGTGTCCAACAGATACGGAACTGCTAAGGTGATAGGCCGCCTGTACGTGAAACAGCCACTGAAAGCC
ACCATCAGTCCCAGGAAGGTTAAAAGCAGCGTGGGTAGCCAAGTTTCCTTGTCCTGCAGCGTGACAGGAA
CTGAGGACCAGGAACTCTCCTGGTACCGCAATGGTGAAATCCTCAACCCTGGAAAAAATGTGAGGATCAC
AGGGATCAACCACGAAAACCTTATAATGGATCACATGGTCAAAAGTGACGGGGGCGCATACCAGTGCTTT…ATT stop!
48
CQ#9: If you were on the jury for the
malpractice trial of the doctor, what
would you decide?
A. The doctor must have done something wrong to
cause cell division to have malfunctioned.
B. The doctor could not have done anything to cause
the problem.
C. It is impossible to tell if the doctor could be at
fault.
49
Case closed?
You’ve presented pretty conclusive evidence that the
clinic was not responsible for causing Down syndrome in
John and Jane’s baby. However, now comes the trickiest
part of the trial. Should the clinic have alerted the couple
that something might be wrong before the baby was
delivered? How could the doctors have known that the
baby might have be born with Down syndrome?
50
How is Down syndrome detected?
Karyotyping
•Isolate chromosomes during fetal cell division.
•Arrange in pairs according to size.
51
CQ#10: When would the best time
be to isolate chromosomes for a
karyotype?
A.
B.
C.
D.
E.
F.
G.
G1
S-phase
G2
Prophase
Metaphase
Anaphase
Telophase
Why would this time be best?
52
CQ#11: Does this person have Down
syndrome?
A. Yes
B. No
53
A karyotype can be performed by collecting cells from the
developing embryo in the first trimester using one of two
procedures. Techniques for doing this slightly increase the risk of
miscarriage (0.5-1.0%). Jane’s family had no history of Down
syndrome, but John had a cousin with the disorder. A chart
showing Jane’s age (red line) and the risk of having a Down
syndrome child is shown below.
54
CQ#12: Is the clinic liable for not
testing for Down syndrome?
A. Yes, the clinic should have tested the baby for Down
syndrome.
B. It is liable only if the clinic failed to follow
suggested guidelines for when to perform the test.
C. Yes, it doesn’t matter if the clinic was at fault or not.
D. No, the clinic should not be held at fault for
something beyond its control.
55
In 2001, France's high court of appeals ruled that the
parents of a boy who has Down syndrome should be
compensated because the situation was not detected by the
doctor during the pregnancy.
In 2004, the Utah Supreme Court ruled that the parents of a
4-year-old girl with Down syndrome cannot sue a doctor
for misreading prenatal tests designed to identify the
disability.
In 2007, a California court awarded a 34-year-old woman
damages because the medical center failed to offer her the
opportunity to undergo amniocentesis and Chorionic Villus
Sampling early in the course of her pregnancy.
56
Historically, women over age 35 or who are at risk of
having a child with Down syndrome are encouraged to
have amniocentesis and CVS to test for this abnormality.
However, because most pregnancies occur in younger
couples, 80% of Down syndrome cases occur with women
under age 35. Down syndrome occurs in one out of every
800-1000 live births.
In 2007, the American College of Obstetricians and
Gynecologists recommended that every pregnant woman,
regardless of age, be offered a choice of tests for this
common birth defect.
57
Image Credits
Unless specifically indicated otherwise below, all illustrations appearing in this case study were created by the author, Norris Armstrong.
Slide 1
Description: Baby feet.
Author: Doreen Dotto ©2006, Doreen Dotto Fine Portrait Photography, Toronto, Ontario, Canada. www.doreendotto.com
Link: Wikimedia Commons, http://commons.wikimedia.org/wiki/Image:Baby_feet.jpg
Clearance: Licensed in accordance with Creative Commons Attribution-Share Alike 3.0 Unported.
Slide 7
Description: An E. coli bacterium was attached to an EM supporting grid and then gently broken open. The DNA in its native form has
spilled out including a small circular plasmid.
Source: Jack Griffith, University of North Carolina.
Clearance: Used with permission.
Slide 8—Left
Description: Metaphase chromosomes.
Author: Steffen Dietzel
Source: Wikimedia Commons, http://commons.wikimedia.org/wiki/File:HumanChromosomesChromomycinA3.jpg
Clearance: Licensed in accordance with Creative Commons Attribution-Share Alike 3.0 Unported.
Slide 8—Right
Description: DNA and chromosome structure.
Source: National Human Genome Research Institute
Link: http://www.genome.gov//Pages/Hyperion//DIR/VIP/Glossary/Illustration/chromosome.cfm
Clearance: Public domain.
Slide 12—Right top
Description: Fluorescently stained dividing cell.
Author: Conly Rieder
Source: National Human Genome Research Institute
Link: http://publications.nigms.nih.gov/moleculestomeds/biology.html
Clearance: This image is a work of the National Institutes of Health, part of the United States Department of Health and Human Services.
As a work of the U.S. federal government, the image is in the public domain.
Slide 14
Description: Replicated chromosome.
Source: Derived from images at Wikimedia Commons: http://commons.wikimedia.org/wiki/File:DNA_replication_split.svg
(Madprime) and http://commons.wikimedia.org/wiki/Image:Chromatin_chromosome.png (Magnus Manske)
Clearance: Licensed in accordance with Creative Commons Attribution-Share Alike 3.0 Unported.
Slide 15
Description: Cell cycle stages.
Source: Wikimedia Commons
Link: http://commons.wikimedia.org/wiki/File:Gray2.png
Clearance: Public domain.
Slide 19 and Slide 20
Description: Human male and female figures.
Source: Wikimedia Commons
Link: http://commons.wikimedia.org/wiki/File:Human.svg
Clearance: Public domain.
Slide 37
Description: Spectral karyotype (SKY).
Source: National Human Genome Research Institute
Link: http://www.genome.gov//Pages/Hyperion//DIR/VIP/Glossary/Illustration/sky.cfm
Clearance: Public domain.
Slide 38
Description: Normal karyotype.
Source: National Cancer Institute
Link: http://visualsonline.cancer.gov/details.cfm?imageid=2721
Clearance: Public domain.
Slide 39
Description: Down syndrome karyotype.
Author: Christa Lese Martin, Department of Human Genetics, Emory University School of Medicine
Source: Emory Genetics Laboratory
Clearance: Used with permission.