Title

Down Syndrome:Down Syndrome: A Multidisciplinary Interactive A Multidisciplinary Interactive Team-based Learning Exercise 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 diseaseThe 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 Exercise

Key Words 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 second-year 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:

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.

“Genetic Disease in a Newborn Female with Multiple Organ System Involvement”

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.

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.

Genetic Disease in a Newborn Female with Multiple Organ System InvolvementGenetic Disease in a Newborn Female with Multiple Organ System Involvement

byStuart Nelson, Ph.D., Paul Koles, M.D., and Diane Bierke-Nelson, CGC

Wright State University Boonshoft School of Medicine

Slide 1

The doctor sends the couple to the regional hospital for consultation at the high- risk 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.

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

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

Diagram XX Diagram YY

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.

Slide 8

The physicians are concerned because the pathophysiology associated with this heart disease can change over time.

QUESTION # 4 : Which statement is true concerning the pathophysiology of the heart defect in MN?

Slide 9

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.

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.

The differential WBC count is:

Slide 12

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 RESULT (%) NORMAL VALUES (%)

blasts 19 0

promyelocytes 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

Wright’s-stained peripheral blood smear from Patient MN

Slide 13

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.

QUESTION # 5 : Which one of the following statements is inaccurate concerning the interpretation of this complete blood count?

Slide 14

A bone marrow biopsy is performed to confirm a presumptive diagnosis. The pathology report states:

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.

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.”

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 maternally-derived HLA were determined to be:

Slide 16

HLA-A2 HLA-B44 HLA-Cw5 HLA-DPB1 HLA-DQ7 HLA-DR1

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

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.

QUESTION # 6 : Which group of three statements represent accurate interpretations of the mixed lymphocyte reaction results?

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

Slide 23

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.

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.

Slide 24

End of Case

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.

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:

Instructor’s Guide

“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:

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:

1) Robbins and Cotran Pathologic Basis of Disease

2) Cecil Textbook of Medicine or an equivalent

3) Stedman’s Medical Dictionary or an equivalent

genetics/molecular biology pathology immunology hematology

To optimize preparation time, instructors will find it useful to review the following notes for each slide:

cardiology neuroscience introduction to clinical medicine clinical diagnosis

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 low-resistance.

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 beta-amyloid 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 beta-amyloid. 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.