Case Teaching Notes for
“Why Is Patrick Paralyzed?”

Introduction / Background

This case study is a “clicker case.” It combines the use of student personal response systems (clickers) with case teaching methods. The case is presented in class using a series of PowerPoint slides punctuated by questions (called “clicker questions”) that students respond to before moving on to the next slide. In this way, students work their way through the material to understand (and usually also solve) the problem presented in the case. Specifically designed for large introductory science classes, the method integrates lecture material, case storylines, student discussion, (clicker) questions, lecture, and the presentation of data in an iterative fashion.

In this case, students encounter a rare genetic disease in which an enzyme is deficient in a critical metabolic pathway, namely, the first step in aerobic respiration. The case challenges students to make connections between energy production, enzymes, and metabolic diseases. Students are exposed to a real-life story (Patrick is my third cousin) that serves as a basis for discussing the uses of energy-rich molecules and the importance of complex metabolic pathways catalyzed by protein enzymes. Overall, students should appreciate the importance of each step in a metabolic pathway as well as the side effects and treatments that can emerge from discovering the underlying enzyme deficiency.

The case was designed for use in a one-semester, majors’ introductory biology course taken primarily by freshmen and sophomores to fulfill a general education requirement. It could however be used in any introductory biology course. Before beginning the case, students should receive a brief introduction to energy and have an understanding of the chemical composition of living organisms.

Objectives

• Understand why energy is necessary for sustaining life (a unifying theme in biology).
• Appreciate the importance of enzymes for catalyzing chemical reactions.
• Recognize that energy conversions are dependent on metabolic pathways.
• Understand the role of enzyme inhibition in metabolic pathways and predict the effects of enzyme deficiency due to genetic disease.
• Apply knowledge of converging metabolic pathways and enzyme inhibition to understand the treatment options for a metabolic disease.

Misconceptions

• The high energy bonds in ATP are strong bonds and difficult to break.
• Glucose is the only source of energy for ATP production by cells.
• Enzymes are always active.

Classroom Management / Blocks of Analysis

Note: The case consists of a series of PowerPoint slides, a number of which have embedded in them links to supporting materials including a video showing Patrick trying to move his head when he was 21 years old (requires RealPlayer or QuickTime) along with a number of animations demonstrating the enzyme/energy relationship, enzyme inhibition, feedback inhibition, and glycolysis.

The case begins by describing what happened to Patrick when he turned 16. It then proceeds to introduce background information about energy, enzymes, and metabolic pathways. The case typically takes two 50-minute lecture sessions to complete, depending on the time for class discussion and the depth of information presented about metabolism. It ends with a discussion of possible treatments for this metabolic disorder.

Teaching the Case

Slide 1, Slide 2, and Slide 3 introduce Patrick and his overall symptoms when his disease had progressed to almost complete loss of motor function.

Slide 4 presents the first clicker question (CQ#1) and asks students to predict the underlying cause of Patrick’s symptoms. Clicker Question #2 in Slide 5 leads to a discussion of energy.

Slide 6, Slide 7, Slide 8, Slide 9, Slide 10, Slide 11, Slide 12, and Slide 13: Since Patrick may suffer from any number of physiological or metabolic deficiencies, a discussion of energy, enzymes, and aerobic metabolism is necessary. Slide 6 summarizes the different types of work that are performed by nerve and muscle cells. In Patrick’s case, these 4 types of work may be affected and causing his disease. For example, if he is unable to synthesize muscle proteins, he will lose his ability to move. If the muscle proteins are unable to slide past each other (mechanical work), resulting in muscle shortening, he cannot move. Cells need to maintain concentration and ion gradients to function properly. Instructors may want to add an image to this slide showing the different types of cellular work. Slide 7 emphasizes the need for cells to have a way to store and release energy to perform work. Movement requires the use of energy, but where does that energy come from and how is it used? Cells store energy in a variety of ways. Patrick’s inability to store energy may be the reason why he cannot move. Alternatively, his ability to release energy from storage may be responsible for his paralysis.

Living organisms are able to maintain their organization through breakdown reactions that lead to the formation of adenosine triphosphate (ATP). ATP provides energy for numerous energy-requiring processes such as establishment of electrochemical gradients and biosynthesis of macromolecules. There is a common misconception that the phosphate bond in ATP (termed the high energy phosphate bond) is a strong bond that releases energy when broken (Slide 8 and Slide 9). Clicker question #3 in Slide 10 addresses this misconception about the “high energy” bond of ATP. Many students will answer that the terminal phosphate bond is a strong bond (hard to break) and releases energy when the bond is broken. However, the correct answer is C: The terminal phosphate bond in ATP is a weak bond that requires little energy to break and releases energy with the formation of new bonds following hydrolysis. Slide 11 provides a graphical representation of the relationship. If Patrick lost his ability to make ATP, neither his muscles nor his neurons would function (Slide 13). For more information about misconceptions about ATP and the “high energy” phosphate bond, see pages 7 and 16 in http://assessment-ws.wikispaces.com/file/view/chemistry-misconceptions.pdf.

Slide 14, Slide 15, Slide 16, Slide 17, Slide 18, Slide 19, Slide 20, Slide 21, and Slide 22: Since Patrick suffers from a metabolic defect, some discussion of enzymes and their regulation is necessary. Enzymes are (usually) proteins that increase the rate of chemical reactions by lowering the activation energy of a reaction without being consumed. They do not alter the energy released or gained following the reaction (Slide 15 and Slide 16—Note: the latter slide includes a link to an animation about enzyme action at http://www.wiley.com/legacy/college/boyer/0470003790/animations/…). Their activity is controlled through both activating and inhibitory mechanisms (instructors may wish to add information on activators).

There are a variety of different types of enzyme inhibition (see the animation link in Slide 18). Metabolic pathways that have branch points are controlled by feedback mechanisms in which the product of the pathway inhibits the branch point enzyme (see animation in Slide 20 that links to http://www.chem.purdue.edu/courses/chm333/enzyme_inhibition.swf). When enzyme activity is inhibited, the substrate levels rise and the products as well as downstream reactants also decline. In branch point pathways, the products in the alternate pathway will also increase (CQ#7 in Slide 22). In addition, changes in the protein sequence may alter enzyme activity, depending on the site of the mutation. The connection between enzymes and Patrick’s paralysis is made in Slide 21.

Slide 23, Slide 24, Slide 25, Slide 26, and Slide 27: Living organisms depend on complex metabolic pathways catalyzed by enzymes to convert food to usable energy. These pathways are regulated by activators or inhibitors depending on the needs of the organism. Glycolysis is a ubiquitous pathway used by many different types of organisms to generate ATP from glucose breakdown. Under anaerobic conditions, the end product of glycolysis, pyruvate, is converted to lactate or ethanol and carbon dioxide (depending on the organism) through fermentation reactions. Fermentation is necessary to reoxidize the coenzymes (Slide 24) produced during glycolysis. In organisms that require oxygen to generate sufficient energy (like us), any downstream inhibition of the aerobic metabolic pathway will result in greater dependence on the fermentation pathway to generate ATP. Humans utilize the lactate fermentation pathway, and downstream block of the conversion of pyruvate to acetyl CoA will lead to lactate and pyruvate accumulation but decreased levels of acetyl CoA. Since lactate is an acid (lactate = lactic acid), this acid buildup in the bloodstream results in a variety of symptoms associated with Patrick’s condition. An abnormal lactate buildup results in nonspecific symptoms (e.g., severe lethargy, poor feeding, rapid breathing), especially during times of illness, stress, or high carbohydrate intake.

Slide 28: This particular slide is rich in detail and contains a custom animation that requires many clicks in “Slide Show” view. I use this animation to go stepwise through the process summarized below. However, instructors can easily modify or completely remove the animation by using PowerPoint‘s Custom Animation task pane, which can be accessed in “Normal” view by going to the menu bar and selecting Slide Show→Custom Animation.

In the presence of oxygen, pyruvate enters the mitochondria and, through a series of metabolic reactions as well as chemiosmotic coupling, generates considerably more ATP compared to glycolysis alone. The critical first step in this pathway is the conversion of pyruvate to acetyl CoA catalyzed by the enzyme pyruvate dehydrogenase (PDH). PDH is a multi-enzyme complex made up of three subunits which catalyzes the five different reactions responsible for the conversion of pyruvate to acetyl CoA. One of those subunits, the enzyme pyruvate dehydrogenase, catalyzes the first reaction which decarboxylates pyruvate (3C) to make a two carbon intermediate. Patrick suffers from a mutation in the enzyme PDH. This leads to a decrease in acetyl CoA from glucose breakdown.

Slide 29, Slide 30, Slide 31, Slide 32, Slide 33, Slide 34, and Slide 35: Pyruvate dehydrogenase complex deficiency (PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. The pyruvate dehydrogenase complex converts pyruvate to acetyl CoA, which then enters the Tricarboxylic (TCA or Krebs) cycle. The loss of PDH activity leads to decreased production of citrate and insufficient ATP production via aerobic metabolism. Although most cells use other sources of energy, such as fatty acids or amino acids, to generate acetyl CoA, the brain depends primarily on glucose for its ATP production. This glucose requirement by the brain leads to severe ATP depletion in PDCD and accounts for Patrick’s loss of function. Symptoms of this disease may include developmental delay, poor muscle tone, abnormal eye movements, or seizures. The magnitude of the energy deficit depends on the residual activity of the enzyme. Thus, Patrick’s paralysis was due to an inherited genetic disease that resulted in the decrease in activity of a critical enzyme in aerobic metabolism.

Depending on the severity of the enzyme mutation, several treatment options are available. Acetyl CoA can be generated by other metabolic pathways, including fatty acid and amino acid break down. Changing the diet from high carbohydrate to low carbohydrate, high fat (ketogenic) diet can lead to increased production of acetyl CoA through fatty acid breakdown. Alternatively, the drug dichloroacetate (DCA) can prevent the conversion of the pyruvate dehydrogenase enzyme from the active to the inactive form, resulting in more enzyme retained in the active conformation. Unfortunately, current therapies are suboptimal for PDCD and, although resolution of the lactic acidosis may occur, cessation of the underlying progressive neurological damage is rare.

Slide 36 recounts what happened to Patrick. Although his family tried to care for him at home, Patrick remained in hospitals and nursing homes until he died in 2006. He died due to pneumonia, sepsis, and renal failure when he was only 21 years old. His family mourns his loss but feels grateful that he was able to survive for four years beyond his doctor’s predictions.

Answer Key

Answers to the questions posed in the case study are provided in a separate answer key to the case. Those answers are password-protected. To access the answers for this case, go to the key. You will be prompted for a username and password. If you have not yet registered with us, you can see whether you are eligible for an account by reviewing our password policy and then apply online or write to answerkey@sciencecases.org.

References

References 1–3 below address student misconceptions about metabolism while references 4–5 provide more clinical information about Patrick’s genetic mutation.

(1) Oliveira, Gabriel A., Sousa, Cristiane R., Da Poian, Andrea T., and Maurício R.M.P. Luz. 2003. Students’ misconceptions about energy-yielding metabolism: glucose as the sole metabolic fuel. Advances in Physiology Education 27: 97–101. Also available at:

http://advan.physiology.org/cgi/reprint/27/3/97.pdf

(2) Storey, Richard D. 1992. Textbook errors and misconceptions in biology: Cell energetics. American Biology Teacher 54 (3): 161–66.

http://bioliteracy.net/misconception.htm

(3) Student Preconceptions and Misconceptions in Chemistry Integrated Physics and Chemistry Modeling Workshop. 2001. Arizona State University.

http://assessment-ws.wikispaces.com/file/view/chemistry-misconceptions.pdf

(4) Frye, Richard E., and Paul J. Benke. 2007. Pyruvate dehydrogenase complex deficiency.

http://emedicine.medscape.com/article/948360-overview

(5) Frye, Richard E., and Paul J. Benke. 2007. Pyruvate dehydrogenase complex deficiency: Treatment and medication.

http://emedicine.medscape.com/article/948360-treatment

Slide Credits

Acknowledgements: I would like to thank the family of Patrick O’Neill, my third cousin, for sharing Patrick’s story with me under very difficult circumstances. In particular, I greatly appreciate the insights from Fr. James O’Neill and his ability to bring hope in times of despair. This material is based upon work supported by the NSF Grant No. DUE-0618570. Any opinions, findings, conclusions, or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of NSF. Special thanks to Eric Ribbens for his insightful review and suggestions for revision.

Date Posted: July 27, 2009.

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