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Mitochondrial Replacement Therapy MITOCHONDRIAL REPLACEMENT THERAPY: FACTORS IN DECISION-MAKING A Thesis Presented to the Faculty of California State University, Stanislaus In Partial Fulfillment of the Requirements for the Degree of Master of Science in Genetic Counseling By Suzanna Tai May 2020 CERTIFICATION OF APPROVAL MITOCHONDRIAL REPLACEMENT THERAPY: FACTORS IN DECISION-MAKING by Suzanna Tai Signed Certification of Approval page is on file with the University Library Sign by email____________________ June 1st 2020__________ Dr. Janey Youngblom, PhD Date Professor of Genetics California State University Stanislaus Sign by email____________________ June 1st 2020__________ Kara Weisiger, MS, CGC Date Genetic Counselor Kaiser Permanente Oakland Sign by email____________________ June 1st 2020__________ Kelsey McClelland, MS, CGC Date Genetic Counselor Myriad Women’s Health © 2020 Suzanna Tai ALL RIGHTS RESERVED ACKNOWLEDGEMENTS I would like to thank the mitochondrial disease community for their participation and support of this research. The vulnerability in sharing your stories to help other families affected with mitochondrial disease is appreciated and needed. This study was funded by California State University Stanislaus’ College of Science Biology Research (BRC) and Student Engagement in Research, Scholarship, and Creative Activity (SERSCA) grants. A sincere thank you to my committee members Kara Weisiger, Kelsey McClelland, and Janey Youngblom for their insight and support during the research and writing process. I would like to express my appreciation to Rebecca Lee for her expertise in qualitative research and analysis. Thank you to the California State University Class of 2020 for the support and encouragement along the way. iv TABLE OF CONTENTS PAGE Acknowledgements .............................................................................................. iv List of Tables ....................................................................................................... vii List of Figures...................................................................................................... viii Abstract ............................................................................................................... ix CHAPTER I. Introduction ........................................................................................ 1 II. Materials and Methods ................. ..................................................... 8 Recruitment ............................................................................ 8 Development of Materials ....................................................... 9 Data Collection - Quantitative ................................................. 10 Data Analysis – Quantitative ................................................... 10 Data Collection – Qualitative .................................................. 11 Data Analysis – Qualitative ..................................................... 11 III. Results................................................................................................ 13 Demographics ......................................................................... 13 Knowledge About Mitochondrial Conditions and MRT .......... 15 Personal Experiences .............................................................. 19 Motivations ............................................................................. 23 Reservations ........................................................................... 27 IV. Discussion .......................................................................................... 35 Influence of Personal Experiences ........................................... 35 Motivations for Own Family ................................................... 35 Broader Benefits ..................................................................... 37 Reservations with Process of MRT ......................................... 38 Societal Concerns ................................................................... 41 Recommendations ................................................................... 44 Limitations.............................................................................. 46 Future Research ...................................................................... 47 v V. Conclusion ......................................................................................... 48 References ........................................................................................................... 49 Appendices A. Participant Letter ...................................................................................... 57 B. Survey ...................................................................................................... 59 C. Interview Guide........................................................................................ 70 vi LIST OF TABLES TABLE PAGE 1. Demographic Information .............................................................................. 13 2. Descriptive Statistical Information on Participants’ Overall Self-rated Knowledge Score on the Survey ....................................................................................... 16 3. Descriptive Statistical Information on Participants’ Average Self-rated Knowledge Score on the General Mitochondrial Topics and Average Self-rated Knowledge Score on MRT Alone .................................................................. 17 4. Dependent Samples Statistical T-test Determining if Difference Between General Mitochondrial Knowledge and MRT-specific Knowledge is Significant ......... 18 vii LIST OF FIGURES FIGURE PAGE 1. Likert Scale .................................................................................................... 16 2. Bar Graph ...................................................................................................... 18 viii ABSTRACT Females affected with mitochondrial disease originating from the maternally inherited mitochondrial DNA (mtDNA) have struggled in the past with the decision to have biological children who are at risk of developing symptoms of mitochondrial disease. Mitochondrial replacement therapy (MRT) was developed as a reliable means of preventing the transmission of mtDNA-based mitochondrial disease to offspring. MRT involves using a donor oocyte as a source of healthy mitochondria, while preserving the intended parent’s genetic link to their child. We examined the decision-making factors that those impacted by mtDNA-based disease would consider about MRT. A quantitative survey was utilized to collect demographic information and gauge participant knowledge about mitochondrial disease and MRT. Qualitative interviews were conducted with eleven people impacted by mitochondrial disease. Participants, although supportive of MRT, were aware of potential risks it may introduce. Included in the findings were the influences of the patient’s personal experiences, motivations to pursue MRT, reservations about MRT, and recommendations surrounding the optimization of MRT from the patient perspective. As MRT is not currently legal or available in the US, it is important to take patient voices into consideration when implementing policies and introducing new therapies into the clinic setting. ix CHAPTER I INTRODUCTION Mitochondrial diseases can be devastating for families, with symptoms that can be debilitating or even result in death. Mitochondrial function is critical for energy production in cells. The organs that are typically most affected are those which rely heavily on this energy production - the heart, brain, muscles, and lungs. However, any organ can be affected by mitochondrial disease. Mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy and ragged red fiber disease (MERRF), and Leber’s hereditary optic neuropathy (LHON) are three examples of mitochondrial disorders due to mitochondrial DNA (mtDNA) variants. Mitochondrial disease can arise from variants within the nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Although the rate of mitochondrial disease is estimated to be 1 in 4000 in the US population (U.S. National Library of Medicine, 2016), 1 in 200 people are estimated to carry a pathogenic mutation in their mtDNA (Elliott et al., 2008). Though these diseases all share their origins in mtDNA, they fall on a wide spectrum of disease severity. LHON is typically considered to be a mtDNA-based mitochondrial disease of lesser severity. Those affected with LHON will present with symptoms in their twenties and thirties, and about 50% of males and 90% of females with a mutation will never show symptoms (Yu-Wai-Man and 1 2 Chinnery, 2000). In contrast, 65-76% of those who are affected with MELAS will present with symptoms at or before age 20, though penetrance is more variable (El- Hattab et al., 2001). Mitochondrial disease caused by mtDNA variants has several unique factors that contribute to variable disease presentation: including maternal inheritance, heteroplasmy and the bottleneck effect. The mitochondria are passed through the maternal line only, part of the oocyte before fertilization. The percent of healthy and variant mtDNA in each oocyte can be unpredictable due to the existence of multiple copies of the mtDNA in each cell. This phenomenon is termed heteroplasmy. Heteroplasmy has been positively correlated to severity of the disease and/or negatively correlated to age of onset of the disease, but is thought to be one of many factors that contribute to severity and age of onset (Zhang
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