Transcript Down Syndrome

Title
Down Syndrome: A Multidisciplinary Interactive
Team-based Learning Exercise
by
Stuart Nelson, Ph.D., Paul Koles, M.D., and Diane Bierke-Nelson*, CGC
Wright State University Boonshoft School of Medicine
Dayton, OH
*Diane Bierke-Nelson is a Certified Genetic Counselor at the
Duluth Clinic/St. Mary’s Health Care System in Duluth, MN.
Description
This educational resource is woven around a newborn female with Down syndrome.
Several associated disorders are explored from a basic science, diagnostic, and
therapeutic standpoint:
a) heart murmur due to a ventricular septal defect that is surgically corrected
to prevent a right-to-left shunt
b) acute leukemia that is treated with a bone marrow transplant following
HLA tissue matching of recipient and donor
c) autopsy findings indicative of Alzheimer disease
The exercise is organized as an unfolding case history with issues developing over
time, reflecting how this genetic disease gradually affects multiple organ systems. A
key feature is that the slides in the case can be presented in sequence; thus the
events unfold over time, mimicking real life. 8 multiple choice questions are inserted
at strategic points in this exercise. Medical students may answer these questions in
teams or as individuals.
Educational goals include an understanding of genetic mechanisms, congenital heart
disease, a complete blood count including interpretation of a peripheral smear, HLA
and bone marrow transplantation, and neurodegenerative disease.
Use of this learning tool encourages collegial interaction, peer-to-peer clarification of
knowledge, and dynamic sharing to arrive at consensus choices.
Educational Objectives
1. Describe the pathogenic mechanism of genetic nondisjunction leading to Down
syndrome
2. Recognize the clinical manifestations of trisomy 21
3. Interpret the abnormalities in a karyotype
4. Identify diseases for which persons with Down syndrome are at increased risk
5. Explain the pathophysiology in a ventricular septal defect, including a left-to-right shunt
and a right-to-left shunt
6. Interpret the results of a complete blood count in acute myelogenous leukemia,
including numerical data and morphologic features in the Wright-stained blood smear
7. Analyze inheritance mechanisms of HLA genes and explain ramifications for tissue
transplantation
8. Recognize the gross and microscopic features of Alzheimer disease
9. Describe the pathogenic mechanisms leading to accumulation of beta-amyloid peptides
in lesions in Alzheimer disease
10. Respect the opinions of others and offer suggestions in a collegial fashion (for teams of
students answering questions by consensus)
11. Make decisions and actively participate in group discussion (for students answering
questions individually)
Learning Resource Type
Key Words
Exercise
team-based learning; Down syndrome; leukemia; congenital
heart disease; Alzheimer; transplantation immunology
Specialty/Discipline Areas
Pathology, Genetics, Molecular Biology,
Immunology, Hematology, Clinical Diagnosis,
Introduction to Clinical Medicine, Cardiology
Effectiveness and Significance of the Work
The authors have field-tested this exercise for 3 years (2003, 2004, 2005) as
part of a team-based learning module in genetic diseases, presented within a
course teaching fundamentals of pathology and pharmacology in the secondyear curriculum at Wright State University Boonshoft School of Medicine.
Suggestions for improvement by students and faculty have been incorporated
to enhance its quality. The pilot trial of this exercise was evaluated as part of a
prospective study comparing team-based learning with case-based group
discussion (Koles, Nelson et. al. Active Learning in a Year 2 Pathology
Curriculum. Medical Education 39: 1045-1055. October 2005.)
Lessens Learned
The exercise consists of 24 slides presenting a story that unfolds over time. It
contains pictures, diagrams, drawings, and tables. Inserted at strategic points in
the case are 8 multiple choice questions.
It works best if the entire case is NOT distributed to medical students in paper
form at the beginning of class or ahead of time. Instead, project the case on a
screen, and allow it to unfold slide after slide. This feature mimics real life, and
our experience has confirmed the effectiveness of this strategy. However, when
answering Question #5, it is helpful for students to have a paper copy of slide 12
(CBC results) in their possession. This allows continuous projection of Question
#5 while participants do calculations on paper.
It is important to use a title that does not reveal which disease(s) this patient
has. Our suggested title is:
“Genetic Disease in a Newborn Female
with Multiple Organ System Involvement”
Teams of students can answer multiple choice questions by raising a card labeled
A, B, C, D, or E to indicate their selection when the question is called. They can
also select their answer on a computer or scantron sheet for grading purposes.
The case is suited for use as an application exercise in team-based learning in
which students reach consensus and then vote as a team. It may be useful to set a
time limit for group discussion so that slower groups do not hinder progression
through the case.
Using an electronic device that instantaneously tabulates results enriches the
learning process. Instructors can then assess and address incorrect responses and
related gaps in knowledge.
Our team-based learning session using this case was 1.25-1.5 hours in length.
In attempting to answer the questions posed in the case, the student or teams of
students should have a few key reference books available, e.g. Robbins and Cotran
Pathologic Basis of Disease, a medicine textbook such as Cecil Textbook of Medicine,
and a medical dictionary.
Faculty should avoid lecturing during this exercise since it is designed to promote
critical thinking and reasoning by students. Instead, probing questions and short
clarification from faculty provide guidance.
Instructors will find it useful to review the Instructors Guide at the conclusion of the
case. This will optimize preparation time.
Genetic Disease in a Newborn Female with Multiple Organ System Involvement
by
Stuart Nelson, Ph.D., Paul Koles, M.D., and Diane Bierke-Nelson, CGC
Wright State University Boonshoft School of Medicine
A family physician in a rural community is providing prenatal care to a pregnant
44-year-old female; the father’s age is 51. The couple delayed seeking health
services during the 1st trimester, so the mother’s serum is tested at 16 weeks
gestation using the “quadruple screen”. The results are shown in this table.
TEST ON MATERNAL SERUM
RESULT
(multiple of median)
NORMAL CONTROL
(multiple of median)
alpha-fetoprotein (AFP)
0.72
1.0
human chorionic gonadotropin (HCG)
1.95
1.0
unconjugated estriol (uE3)
0.73
1.0
inhibin A
2.05
1.0
The doctor sends the couple to the regional hospital for consultation at the highrisk perinatal center. Fetal ultrasound detects increased nuchal translucency. An
amniocentesis is done, and cells in the amniotic fluid are subjected to
cytogenetic analysis. The results of these chromosomal studies are shown on
the next slide.
Slide 1
Slide 2
QUESTION # 1 : Which genetic mechanism led to the abnormality seen in
cytogenetic studies on MN?
A
When homologous #21 chromosomes paired up in the primary oocyte, a
triplet-repeat mutation produced a 3rd #21 chromosome. At meiosis, two of
the #21 chromosomes were placed in the ovum. Then a normal sperm with
one #21 chromosome fertilized the abnormal ovum.
B
When homologous #21 chromosomes paired up in the primary oocyte,
maternal imprinting produced a 3rd #21 chromosome. At meiosis, two of the
#21 chromosomes were placed in the ovum. Then a normal sperm with one
#21 chromosome fertilized the abnormal ovum.
C
When homologous #21 chromosomes paired up in the primary oocyte, a
nondisjunction during meiosis placed both #21 chromosomes in the ovum.
Then a normal sperm with one #21 chromosome fertilized the abnormal ovum.
D
When homologous #21 chromosomes paired up in the primary spermatocyte,
paternal imprinting produced a 3rd #21 chromosome. At meiosis, two of the
#21 chromosomes were placed in a sperm. Then this abnormal sperm
fertilized a normal ovum.
E
When homologous #21 chromosomes paired up in the primary oocyte,
uniparental disomy during meiosis created an ovum with two #21
chromosomes. Then a normal sperm with one #21 chromosome fertilized the
abnormal ovum.
Slide 3
Baby MN is born at 40 weeks gestation. Physical examination of the hands
detects a characteristic often seen in patients with MN’s genetic disease. A
diagram of MN’s left hand is shown below. The diagram on the right
represents hand characteristics common in the general population.
MN’s left hand
Slide 4
QUESTION # 2 : Ophthalmic examination is likely to show which
pathology in MN?
A. Pupils that are not round due to defective formation of the iris
B. Speckled rings at the periphery of the irides
C. Sclerae that have a bluish discoloration
D. Nodules of tissue in the irides
E. Bilateral upward and outward displacement of the lenses
Slide 5
Upon cardiac auscultation
during the first year of life,
an abnormal heart sound is
evident.
Diagnostic imaging studies
of the heart indicate the
presence of a congenital
anomaly illustrated in this
diagram.
Slide 6
QUESTION # 3 : What type of abnormal heart sound is this defect
likely to produce?
A. Pansystolic murmur with peak intensity in mid-systole
B. Machinery-like murmur heard throughout systole and
diastole
C. Mid-systolic click
D. Pandiastolic murmur diminishing in intensity from early
to late diastole
E. Early systolic murmur transmitted to the carotid arteries
Slide 7
The physicians are concerned because the pathophysiology associated with
this heart disease can change over time.
Diagram XX shows the
pathophysiology of MN’s
defect during her first
year of life.
Diagram YY shows the
pathophysiology of MN’s defect that
might occur later in life if the defect is
not corrected.
Diagram XX
Diagram YY
Slide 8
QUESTION # 4 : Which statement is true concerning the
pathophysiology of the heart defect in MN?
A. In Diagram XX, the pressure in the right ventricle is greater
than the pressure in the left ventricle.
B. The pathophysiology in Diagram XX will cause hypoxemia
with a decreased pO2.
C. Shunt reversal, as shown in Diagram YY, occurs because
irreversible pulmonary vascular disease and decreased
pulmonary arterial pressure are present.
D. The pathophysiology in Diagram YY will lead to central
cyanosis.
E. A defect in the membranous region of the septum is more
likely to close spontaneously than a defect in the muscular
septum.
Slide 9
At 12 months of age, a membranous ventricular septal defect is
surgically repaired to prevent irreversible pulmonary vascular
disease, pulmonary arterial hypertension, and reversal of the shunt.
The heart surgery is a success, and the patient remains in adequate
health over the years with annual physicals to monitor status.
At the age of 36, MN comes to the clinic complaining of fatigue and
malaise.
Physical examination reveals multiple petechiae on the skin. The
patient’s oral temperature is 100.2º F.
Slide 10
A complete blood count (CBC) is performed as shown here.
Slide 11
These tables contain the results of the CBC. Remarkable findings in the
peripheral blood smear are on the next slide.
TEST
RESULT
NORMAL VALUES
hemoglobin
9.0 g/dL
13 - 18 (males); 12 - 17 (females)
hematocrit
31%
43 - 52 (males); 37 - 51 (females)
WBC count
2000/L
4000 - 10,500
platelet count
40,000/L
150,000 - 450,000
CELL TYPE
The
differential blasts
WBC count
promyelocytes
is:
RESULT (%)
NORMAL VALUES (%)
19
0
1
0
metamyelocytes
2
<1
segmented neutrophils
3
45 - 79
lymphocytes
60
16 - 47
monocytes
12
0-9
eosinophils
2
0-6
basophils
1
0-3
Slide 12
Wright’s-stained peripheral blood smear from Patient MN
Slide 13
QUESTION # 5 : Which one of the following statements is inaccurate
concerning the interpretation of this complete blood count?
A. The decreased platelet count will cause a deficiency in primary
hemostasis leading to susceptibility to bleeding.
B. The thin rod-like structures seen in the cytoplasm of the blast
cells in the peripheral blood smear are characteristic of an
acute myelogenous leukemia (AML).
C. MN’s absolute lymphocyte count of 1200/L is elevated above
the upper limit of normal.
D. MN has anemia as suggested by the decreased hemoglobin
concentration and decreased hematocrit.
E. An immunophenotype of CD33-positive and terminal
deoxynucleotidyltransferase (TdT)-negative would provide
evidence that the blast cells in the peripheral blood smear are
immature myeloid cells.
Slide 14
A bone marrow biopsy is performed to confirm a presumptive
diagnosis. The pathology report states:
PATHOLOGY REPORT: “Hypercellular marrow with
confluent sheets of blastic cells replacing normal fat.
Flow cytometry and morphologic features are
consistent with acute myelogenous leukemia (AML)
with maturation.”
MN’s leukemia remits after combination chemotherapy, and she is
doing quite well over the next 5 years. However, at age 41 she
relapses.
A bone marrow transplant is suggested to counteract the effects
of leukemia, and MN’s 3 brothers all volunteer to act as donors.
Slide 15
MN and one of her brothers may
have identical HLA (human
leukocyte antigen) genes. The
diagram on the right illustrates
how these genes are inherited.
MN inherited one set (haplotype)
of 6 HLA genes (designated
HLA-A, B, C, DP, DQ, DR) from
her mother. She inherited
another set (haplotype) from her
father.
For example, MN’s maternallyderived HLA were determined to
be:
HLA-A2
HLA-B44
HLA-Cw5
HLA-DPB1
HLA-DQ7
HLA-DR1
Slide 16
Tissue typing and matching proceeds. In the mixed lymphocyte
reaction, MN’s lymphocytes are rendered non-proliferative by
subjecting them to mitomycin C. These treated cells are placed in 3
culture plates. Then:
Brother X’s untreated lymphocytes are added to the 1st plate
Brother Y’s untreated lymphocytes are added to the 2nd plate
Brother Z’s untreated lymphocytes are added to the 3rd plate
Each mixed lymphocyte reaction is observed to see if proliferation
of lymphocytes occurs.
The results are on the next slide.
Slide 17
Slide 18
QUESTION # 6 : Which group of three statements represent accurate
interpretations of the mixed lymphocyte reaction results?
1.
Brother Y and Brother Z are both HLA-histocompatible with MN.
2.
If Brother X is used as a donor, then an acute transplant rejection will
occur.
3.
Brother X and Brother Z have different HLA antigens.
4.
Brother Y and Z have identical HLA antigens.
5.
Brother X and MN have identical HLA antigens.
6.
If Brother Y is used as the donor, then a graft versus host reaction is
likely to occur.
Choices
A. Statements 1, 2, 6
D. Statements 2, 3, 5
B. Statements 1, 4, 6
E. Statements 3, 5, 6
C. Statements 2, 3, 4
Slide 19
MN expires at age 43 despite the bone marrow transplant from
Brother X and cancer chemotherapy.
An autopsy is performed, and the brain is examined.
The pathologist observes moderate atrophy of cerebral gyri, with
widening of the sulci. These atrophic changes are most prominent
in frontal and temporal lobes.
Slide 20
Representative tissue sections are submitted for microscopic study.
The photomicrograph below is a Bielschowsky stain of cerebral cortex, and it
shows frequent lesions (marked by arrow) present in greater numbers than
would be expected in normal age-matched individuals.
Slide 21
QUESTION # 7 : What clinical manifestation is common in the
neurologic disease seen in MN’s brain tissue?
A. Dementia
B. Startle myoclonus
C. Bitemporal hemianopia
D. Pill-rolling tremor
E. Choreoathetosis
Slide 22
This case is discussed at Grand Rounds, and the presenter is
asked to address the relationship between Down syndrome and
increased susceptibility to Alzheimer disease.
Slide 23
QUESTION # 8 : Why do people with Down syndrome have increased
susceptibility for Alzheimer disease?
A
Chromosome #21 contains the genetic locus that is responsible for
production of presenilin proteins. An “extra” chromosome #21 leads to
increased production of presenilins that function to cleave amyloid
precursor protein (APP) into beta-amyloid.
B
Chromosome #21 contains the genetic locus that is responsible for the
production of amyloid precursor protein (APP). An “extra” chromosome
#21 leads to increased production of APP which can then be cleaved by
beta-secretase and gamma-secretase into beta-amyloid.
C
Chromosome #21 contains the ApoE genetic locus. An epsilon-4 allele at
this locus is responsible for production of ApoE protein. An “extra”
chromosome #21 leads to increased production of ApoE protein that binds
readily to beta-amyloid in neuritic plaques.
D
Chromosome #21 contains the genetic locus that is responsible for the
production of tau protein. An “extra” chromosome #21 leads to increased
production of tau protein that becomes hyperphosphorylated, creating
neuritic plaques.
End of Case
Slide 24
References
1. Koles P, Nelson S, Stolfi A, Parmelee D, DeStephen D. Active learning
in a Year 2 pathology curriculum. Medical Education 39: 1045-1055.
October 2005.
2. Kumar V, Abbas A, Fausto N. Robbins and Cotran Pathologic Basis of
Disease. 7th ed. Elsevier Saunders. 2005.
3. Tierney L, McPhee S, Papadakis M. Current Medical Diagnosis &
Treatment. 43rd ed. Lange Medical Books/McGraw-Hill. 2004.
4. Nussbaum R, McInnes R, Willard H. Thompson & Thompson Genetics
in Medicine. 6th ed. Saunders. 2004.
5. Wallach J. Interpretation of Diagnostic Tests. 7th ed. Lippincott
Williams & Wilkins. 2000.
6. Parham P. The Immune System. 2nd ed. Garland Science. 2005.
Instructor’s Guide
Allow 1.25-1.5 hours for the session.
It works best if the entire case is NOT distributed to medical students in paper form
at the beginning of class or ahead of time. Instead, project the case on a screen,
allowing it to unfold slide after slide. This feature mimics real life, and field-testing
has confirmed that this strategy works well.
It is important to use a title that does not reveal the diagnosis. Our suggested title
is:
“Genetic Disease in a Newborn Female
with Multiple Organ System Involvement”
When a multiple choice question appears in the case, allow time for students or
teams of students to discuss the choices with their colleagues, check reference
books, and choose an answer. Then ask students to indicate their answer by one or
more of the following techniques:
 a show of hands for A, B, C, D, or E
 raising a card labeled A, B, C, D, or E
 indicating the answer on a computer
 indicating the answer on a paper grading sheet
 use an electronic device that instantaneously tabulates answers
The most helpful reference books for answering questions posed in this case are:
1) Robbins and Cotran Pathologic Basis of Disease
2) Cecil Textbook of Medicine or an equivalent
3) Stedman’s Medical Dictionary or an equivalent
It may be useful to set a time limit for discussion so that students learn to be
decisive. In our team-based learning application exercises, we allow 3 additional
minutes once the majority of teams have reached consensus.
After the students have chosen their answers, reveal the correct response and clarify
any area of confusion. However, it is best to avoid lecturing during this exercise
since it is designed to promote active learning.
The content of this educational tool makes it suitable for use in the following courses
or disciplines:
genetics/molecular biology
pathology
immunology
hematology
cardiology
neuroscience
introduction to clinical medicine
clinical diagnosis
To optimize preparation time, instructors will find it useful to review the following
notes for each slide:
Slide 1 The students should recognize the key elements in this history. The
advanced maternal age implies an increased risk of Down syndrome. The table
shows reduced levels of alpha-fetoprotein, reduced levels of unconjugated estriol,
elevated levels of human chorionic gonadotropin, and elevated levels of inhibin A.
These results point toward the possibility of a cytogenetic disorder such as Down
syndrome.
Slide 2 The karyotype shows the presence of three #21 chromosomes. Also note the
two X chromosomes giving rise to a female phenotype.
Slide 3 The answer to QUESTION #1 is C. The statements in answer C describe a
nondisjunction genetic event that occurs during meiosis. This is the most common
mechanism leading to Down syndrome.
Side 4 The diagram of Patient MN’s hand shows a simian crease. Note that the hand
on the right shows two creases across the palm.
Slide 5 The answer to QUESTION #2 is B.
Choice B is a description of Brushfield spots, a characteristic seen in Down syndrome
(trisomy 21).
Choice A is a description of coloboma or keyhole pupil, a characteristic of Patau
syndrome (trisomy 13).
Choice C is a description of blue sclerae, a characteristic of osteogenesis imperfecta.
Choice D is a description of Lisch nodules, a characteristic of neurofibromatosis.
Choice E is a description of ectopic lentis, a characteristic of Marfan syndrome.
Slide 6 The diagram shows a ventricular septal defect (VSD).
Slide 7 The answer to QUESTION #3 is A. A ventricular septal defect will often lead
to a pansystolic (also called holosystolic) heart murmur. A machinery-like murmur
can be heard in patent ductus arteriosus. A mid-systolic click is associated with
mitral valve prolapse. A pandiastolic murmur could represent aortic regurgitation.
Aortic stenosis can cause a systolic murmur that transmits to the carotid arteries.
Slide 8 Diagram XX demonstrates left-to-right shunting of blood in a ventricular
septal defect. The Diagram YY shows right-to-left shunting of blood in VSD.
Slide 9 The answer to QUESTION #4 is D.
Diagram XX illustrates a left-to-right shunt that occurs early in ventricular septal
defect. Blood flows from the left ventricle through the defect into the right ventricle
because the pressure is greater on the left side than that on the right. Remember
that normal pulmonary circulation is characterized as low-pressure and lowresistance.
This left-to-right shunt however, causes abnormally high blood volume in the
pulmonary arteries. Eventually, small arterioles in the lung suffer irreversible injury
and create increased resistance to blood flow. As pulmonary arterial pressure
progressively increases (i.e. pulmonary hypertension), it ultimately becomes easier
for blood to flow toward the left ventricle, resulting in a right-to-left shunt as shown
in Diagram YY.
The left-to-right shunt in Diagram XX allows blood to be oxygenated, so the partial
pressure of oxygen is sufficiently above the level that would be associated with
hypoxemia.
The right-to-left shunt in Diagram YY causes venous blood to bypass the lungs,
remaining deoxygenated, and central cyanosis occurs. A good indicator of central
cyanosis is a bluish-purplish discoloration of the oral mucosa.
Finally, large defects that fail to close spontaneously are usually found in either the
membranous or infundibular region. In contrast, many smaller defects that can close
spontaneously are found in the muscular region of the septum.
Slide 10 Down syndrome patients are at an increased risk to develop acute leukemia.
The leukemia is most often either acute lymphoblastic leukemia (ALL) or acute
myelogenous leukemia (AML). The signs/symptoms described on this slide would be
consistent with the onset of one of these cancers.
Slide 11 A brief visualization of how a complete blood count (CBC) is performed.
Slide 12 These are the results of the CBC. Note that the patient is anemic as
indicated by the decreased hemoglobin concentration and the decreased hematocrit.
The patient also has low numbers of platelets and low numbers of white blood cells.
The differential WBC count is remarkable for the presence of immature WBCs. Even
though the differential is skewed with regard to lymphocytes, this does not indicate
an elevated absolute lymphocyte count. The absolute lymphocyte count is 2000 x .60
= 1200, near the lower limit of normal.
Slide 13 The arrow points to an Auer rod in the cytoplasm of a blastic WBC; this is
one characteristic of acute myelogenous leukemia (AML).
Slide 14 The answer to QUESTION #5 is C. An important point to note on this slide is
that neoplasms of WBCs can be categorized by cell surface markers. CD33 is a
marker for immature myeloid cells. TdT is a marker for immature (precursor) B cells
and immature (precursor) T cells.
Slide 15 The pathology report is noteworthy in that blastic leukocytes have
accumulated in the bone marrow, obliterating the normal fat and hematopoietic tissue.
Slide 16 The diagram illustrating the inheritance of HLA genes shows that the mother
of MN had a 50% chance of giving MN the chromosome #6 containing the “purple” set
(haplotype) of HLA genes and a 50% chance of giving MN the chromosome #6
containing the “green” set of HLA genes.
Likewise, the father had a 50% chance of giving MN “red” and a 50% chance of giving
MN “blue”. NOTE: A set or haplotype of HLA genes does not mean that the HLA-A is
identical to the HLA-B, etc. Haplotype simply implies a set of closely-linked genetic
loci on a chromosome.
Slide 17 The mixed lymphocyte reaction can detect HLA differences between
individuals. For example, if Brother X has HLA similarities to MN, then Brother X’s
lymphocytes will not proliferate because they do not recognize MN as foreign. On the
other hand, if Brother Y has different HLA antigens than MN, then Brother Y’s cells will
proliferate in response to the foreign HLA antigens on MN’s lymphocytes.
Slide 18 The results of the mixed lymphocyte reactions indicate that Brother X has
HLA antigens identical to MN. MN is foreign to both Brother Y and Brother Z.
Slide 19 The answer to QUESTION #6 is E.
There are three true statements in this table: 3,5,6
There are three false statements in this table: 1,2,4
The task is to pick the answer that contains three true statements.
This type of question has worked well for us. However, trial-and-error has revealed
that there should be no more than six statements in the table; three should be true,
and three should be false.
Brother Y and Z detect foreign HLA antigens on MN’s lymphocytes and respond by
cell division in the mixed lymphocyte reaction. An important point is that infusion of
Brother Y’s or Z’s bone marrow into MN could lead to graft versus host (GVH)
disease. MN is not immunocompetent, and foreign bone marrow acts like an
immunocompetent tissue, attacking the recipient.
Brother X’s HLA antigens are identical to MN’s HLA antigens as indicated by the lack
of cell division in the mixed lymphocyte reaction. Evidently, both received the same
#6 chromosome from their mother and the same #6 chromosome from their father.
There are two reasons that infusion of bone marrow from brother X would not cause
an acute transplant rejection: 1) MN would not recognize Brother X’s tissues as
foreign, and 2) MN is not immunocompetent because leukemic cells in the bone
marrow have most likely impaired her immune system.
Slide 20 Almost 100% of Down syndrome patients who reach their 5th decade of life
are likely to have Alzheimer disease. Gross lesions in the brain reveal atrophy of the
cerebral cortex in the frontal and temporal lobes.
Slide 21 The picture is a section of cerebral gray matter stained with Bielschowsky
stain. The arrow points to a neuritic plaque (senile plaque).
Slide 22 The answer to QUESTION #7 is A.
Dementia is a clinical manifestation of Alzheimer disease.
Startle myoclonus is a clinical manifestation of Creutzfeldt-Jacob disease.
Bitemporal hemianopia is a clinical manifestation of a mass lesion in the pituitary
gland that compresses the optic chiasm.
Pill-rolling tremor is a clinical manifestation of parkinsonism.
Choreoathetosis is a clinical manifestation of Huntington disease.
Slide 23 The correlation between Down syndrome and Alzheimer disease is due to
the presence of three #21 chromosomes.
Slide 24 The answer to QUESTION #8 is B. The gene that produces amyloid
precursor protein (APP) is located on chromosome #21. Down syndrome patients
have an extra #21 chromosome, so they are thought to produce more amyloid
precursor protein (APP). The APP can be metabolized in such a way that betaamyloid is generated. Beta-amyloid is pathologic and is a major component of
neuritic (senile) plaques.
The other choices represent some very important mechanisms that lead to neuritic
(senile) plaques and/or neurofibrillary tangles:
 Presenilin proteins are produced from chromosome #1 and chromosome
#14. When mutations occur in the genes that produce these proteins,
increased levels of pathologic beta-amyloid are generated.
 If the ApoE gene on chromosome #19 has the epsilon-4 allele, then the
ApoE protein generated from this locus readily binds to pathologic betaamyloid. Through some as yet unknown mechanism, this contributes to
increased neuritic plaque formation.
 In Alzheimer disease, normal tau proteins in axons become
hyperphosphorylated, leading to formation of neurofibrillary tangles, not
neuritic plaques.