Chapter 1. An Unexplained Death

Instructor Notes for “An Unexplained Death”, Carbohydrate Metabolism Case Study

Topic Pre-requisites: Students should have exposure to the topics of Chapters 14 and 16 in Lehninger POB, 6^th ed.

Overview

This case is designed to help students understand the importance of vitamins as precursors of coenzymes as well as to provide a context to review the reactions of glycolysis, the pentose phosphate pathway, the pyruvate dehydrogenase complex, and the citric acid cycle. As such, we have anticipated that students will have been exposed to material in the textbook through Chapter 16 of Lehninger POB, 6^th ed.,before beginning the case (Chapters 14 and 16 are essential).

Students may work individually or in groups to complete this case study. Students are constantly encouraged to refer to their textbook throughout the case, and internet access is permitted, although it is not necessary for the completion of the case. Students are required to iteratively acquire, analyze, and integrate data as they progress through the case and answer assessment questions found throughout the case. All assessment questions are automatically scored.

The case will also keep track of the number of investigations that students conduct and report this number to the instructor; students are made aware of this fact as a means to encourage careful consideration of investigation options and discourage guessing. It is entirely up to the instructor what to do with this information; we suggest potentially rewarding students who solve the case efficiently and/or penalizing students who obviously used blanket guessing (evident by the use of all or nearly all investigative options). For reference: there are 29 total investigative options within the case and 8 are minimally required to complete the case. We anticipate that careful students will typically make use of 12 to 20 options in solving this case.

Finally, there is an optional section called “Extending your understanding beyond the case” that instructors may choose to include or exclude from the case. As the title implies, these questions extend to related information in the textbook but are not critical to the case itself. When assigning the case, you will be asked whether you would like to include this material.

Learning Objectives

This case is intended for remediating or extending student capabilities in these difficult topics:

1. The real-world application of the study of human metabolism. Student will:
   • utilize real biochemical tests to evaluate and “solve” a metabolic disorder case.
   • consider the importance of factors like personal and family history, diet, medications taken, and symptoms in solving a biochemical case.
     • explain why alcohol abuse can result in vitamin deficiency.
2. Critical aspects of human central metabolism. Students will:
   • review reactions of
     • glycolysis
     • the pentose phosphate pathway
     • the pyruvate dehydrogenase complex (including cofactors involved)
     • the citric acid cycle (with consideration of reversible vs. irreversible reactions)
   • understand the role of vitamins as precursors of coenzymes.
   • Appreciate the importance of coenzymes in enzyme function and human health.
     • explain how vitamin deficiency can cause disease.
     • explain the importance of thiamine, specifically in heart and brain function.
3. Practice critical thinking skills involving data. Students will:
   • evaluate data provided by metabolite and enzyme tests.
   • integrate multiple pieces of biochemical data.

Some questions are designed to show areas of difficulty for students

• The case connects a behavior (alcohol abuse) to specific organ failure. Students may find it challenging to connect all the dots. Our intention is to demonstrate how behavioral choices may lead to vitamin deficiency, how vitamin deficiency can lead to a loss of specific enzyme function (a connection to Chapter 6 of Lehninger POB, 6th ed.), and how tissue-specific differences in metabolic needs may then lead to specific organ failure.
• The reason why beriberi often leads to heart failure may be unclear to students.
• The description of Wernicke-Korsakoff syndrome in the textbook (page 580 in Lehninger POB, 6th ed.) provides an additional interesting perspective on vitamin deficiencies--specifically, that additional genetic polymorphisms influence the way different people respond to the same physical challenges. In this case, mild beriberi causes profound mental deficiencies in people with these polymorphisms. Some of the assessment questions in the optional “Extending your understanding beyond the case” section address this interesting but complex issue.
• Some of the assessment questions in the optional “Extending your understanding beyond the case” section present an opportunity to point out the physiological reversibility of some of the reactions of the citric acid cycle, an often overlooked aspect of the cycle.
• Author note: A common error is to jump immediately into testing a ‘pet’ hypothesis by conducting laboratory tests (metabolite assays or enzyme assays) before exploring “data gathering” options like visual inspections, an autopsy, or interviews with people who knew the victim. This is an excellent and intentionally designed opportunity to point out a common mistake about the scientific method--that is, it begins with making careful observations, rather than by immediately testing quickly formed hypotheses.

Suggested implementation

Below we describe two options for course implementation. The hybrid Online/In-class approach is recommended. Time required for students to complete the online case will vary by group depending on the level of discussion between each investigation. The case study can be started and stopped, and so it is recommended to give students a window of 2 to 3 days in which to complete the assignment.

1. Share the case study link with your students to work online outside of class, preferably in pairs or groups of three. Assign the case study to be due before your next class meeting. Students should be instructed to bring copies of notes and/or printed answers to assessment questions to the following class period.
2. Review the online answers before the following class for difficult areas for students (see expected areas of difficulty above).
3. Lead students in a discussion in pairs, groups, or as a class (depending upon class size and instructor preference) to address unresolved difficulties (~30 minutes in-class time).
4. We recommend that you select questions from the supplied assessment questions to use on exams or as homework assignments to reinforce the difficult concepts covered. Please see document “Exam Questions for Case 2: Carbohydrate Metabolism.”

1. Share the case study link with your students to work online, preferably in pairs or groups of three. Assign the case study to be due before your next class meeting.
2. Review the online answers for difficult areas for students (see expected areas of difficulty above).
3. Mention or remediate tough points during a portion of lecture.
4. We recommend that you select questions from the supplied assessment questions to use on exams or as homework assignments to reinforce the difficult concepts covered. Please see the document “Exam Questions for Case 2: Carbohydrate Metabolism.”

Suggestions for in-class discussions (these questions may also be used in summative assessments-- i.e., exams, scored quizzes, etc.):

• What were some of the most important facts about the case that were revealed without the use of specific enzyme tests?
  • Students could be directed to brainstorm in groups or as a whole class.
• Why was it important to examine the activity of the three enzymes that make up the PDH complex individually and how did the information you acquired from this test help you solve the underlying problem?
• How does alcoholism relate to this case?
  • Students could be directed to brainstorm in groups or as a whole class.
• What are the similarities between the pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase both in terms of the enzymes that catalyze the reactions and in terms of the types of reactions each catalyzes?
• Why does beriberi cause heart failure?
  • Could be easily used as a think-pair-share exercise.
  • Alternatively, students could first answer this question individually in writing, and then those responses could be collected or discussed in groups and revised.

Note: the final two discussion points refer to the optional questions at the end of the case that may be assigned and completed online at the discretion of the instructor.

• What is Wernicke-Korsakoff syndrome and how does it relate to this case? Is this syndrome the cause of the person’s death in this case? Why or why not?
  • Could be easily used as a think-pair-share exercise.
  • Alternatively, students could first answer this question individually in writing, and then those responses could be collected or discussed in groups and revised.
• The last assessment question of the case was particularly challenging. Form a group to discuss and answer this question. Why is it that when there are inborn errors in either α-ketoglutarate dehydrogenase, succinate dehydrogenase, or fumarase, the levels of α-ketoglutarate in the urine tends to rise no matter which of the three enzymes is defective?
  • Group work is suggested here due to the difficulty of the question.

You are missing vital information

You are missing vital information to sufficiently explain this incident. You may be overlooking factors related to this man’s physiological state at the time of his death or your investigation may not be detailed enough. Review your options and try to select additional options to either discover new physiological abnormalities or to explore more deeply any that you have already uncovered. Try to think about what details you still cannot fully explain.

You are missing vital information

You are missing vital information to sufficiently explain this incident. You may be overlooking factors related to this man’s physiological state at the time of his death or your investigation may not be detailed enough. Review your options and try to select additional options to either discover new physiological abnormalities or to explore more deeply any that you have already uncovered. Try to think about what details you still cannot fully explain.