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Hira Peracha a Thesis DIAGNOSIS METHOD FOR MUCOPOLYSACCHARIDOSES by Hira Peracha A thesis submitted to the Faculty of the University of Delaware in partial fulfillment of the requirements for the degree of Bachelor of Arts in Biological Sciences with Distinction Spring 2018 © 2018 Hira Peracha All Rights Reserved i DIAGNOSIS METHOD FOR MUCOPOLYSACCHARIDOSES by Hira Peracha Approved: __________________________________________________________ Shunji Tomatsu, MD, Ph.D. Professor in charge of thesis on behalf of the Advisory Committee Approved: __________________________________________________________ Deni Galileo, Ph.D. Professor in charge of thesis on behalf of the Advisory Committee Approved: __________________________________________________________ Jessica Tanis, Ph.D. Committee member from the Department of Department Name Approved: __________________________________________________________ Barbara Settles, Ph.D. Committee member from the Board of Senior Thesis Readers Approved: __________________________________________________________ Michael Chajes, Ph.D. Chair of the University Committee on Student and Faculty Honors ii “Education is the key to unlocking the world, a passport to freedom.” -Oprah Winfrey iii ACKNOWLEDGMENTS I dedicate my thesis to my late grandfather, who taught me the value of life, hard work and sacrifice- especially in sickness and in health. I would like to express my deepest acknowledgements to my family. I could not have achieved all of my dreams and goals in life without my parents; my mom and my dad, whose sacrifices, love and support have been endless and infinite. Thank you for raising me to believe that anything was possible, and for spending your entire lives to better mine. To my younger siblings, Saarah, Hafsah and Arif, who have been the light in the dark times in my life and have always brought joy and happiness in my life. To my grandparents, who have always prayed for my success and keep pushing me to further myself in life. I would like to acknowledge my professor and advisor, Dr. Shunji Tomatsu, for all of your endless mentoring, patience and for shaping me into a young researcher and successful woman that I am today. Dr. Tomatsu, you took me when I was very young in my undergraduate career, and you have always believed in me, especially when I had barely any experience in research. I have become such a bright researcher, and have had so many opportunities arise from working with you. iv I would like to thank my committee members, Dr. Deni Galileo, Dr. Jessica Tanis, and Dr. Barbara Settles, who without their support and encouragement, my thesis could not be possible. Thank you for guiding me every step of the way. I would like to thank all of my current and previous lab members for their support, guidance and help. The past three years could not have been possible without my lab mates: Shaukat, Kazuki, Molly, Francyne, Caitlin, Melodie, Nivi, and Hui- Huan, thank you for all of your help every step of the way. Francyne, Caitlin, Molly and Melodie, I not only gained the most amazing friends ever through our lab but I also gained a family. You girls shaped me to the woman I am today, teaching me always about women empowering other women. Through every stage of my life you girls have been there for me, helping me to do better and bigger things in life, and for showing me that there are no boundaries to dreams. I have never been as inspired or motivated by anyone except for you four girls. I am literally blessed for such an amazing team. I would like to thank my best friends, Kiran, Areeba, Ifra, Safiyah and Ayesha. You girls have helped me, supported me and encouraged me to do more in my life and pushed me to challenge myself to become a better person every day. In times of need and in times of joy, I know you girls will always be there. I am where I am today, because of you all, and I could not have accomplished all that I have so far without you. Thank you for everything. Here’s to a lifetime of friendship ahead. v Lastly, I would like to thank Nucleus, Delaware INBRE, Nemours COBRE, and the Undergraduate Research Program of University of Delaware for all of the funding and support to make my undergraduate research possible. vi LIST OF TABLES ......................................................................................................... xi LIST OF FIGURES ..................................................................................................... xii ABSTRACT .............................................................................................................. xviii INTRODUCTION .......................................................................................................... 1 1.1 Lysosomal Storage Disorders .................................................................... 1 1.2 Mucopolysaccharidosis (MPS) .................................................................. 4 1.3 Types of MPS ............................................................................................ 6 1.3.1 MPS I (Hurler, Hurler/Scheie, Scheie syndrome) ......................... 6 1.3.2 MPS II (Hunter Syndrome) ............................................................ 7 1.3.3 MPS III (Sanfilippo Syndrome) ..................................................... 8 1.3.4 MPS IV (Morquio Syndrome) ....................................................... 9 1.3.5 MPS VI (Maroteaux-Lamy Syndrome) ......................................... 9 1.3.6 MPS VII (Sly syndrome) ............................................................. 10 1.3.7 MPS IX (Natowicz Syndrome) .................................................... 11 1.4 MPS Age Diagnosis ................................................................................. 11 1.5 Glycosaminoglycans (GAGs) .................................................................. 20 1.6 Aims of This Study .................................................................................. 22 EPIDEMIOLOGY OF MUCOPOLYSACCHARIDOSIS ........................................... 23 2.1 Birth prevalence vs. Incidence of MPS .................................................... 23 2.2 Birth Prevalence of MPS in Japan: .......................................................... 24 2.2.1 Method: ........................................................................................ 24 2.2.2 Results: ......................................................................................... 24 2.3 Birth Prevalence of MPS in Switzerland ................................................. 26 2.4 Other countries ......................................................................................... 27 2.4.1 Birth Prevalence of MPS in Saudi Arabia ................................... 28 2.4.2 Birth Prevalence of MPS in Taiwan ............................................ 28 2.4.3 Birth Prevalence of MPS in South Korea .................................... 29 2.4.4 Incidence of MPS in China .......................................................... 29 2.4.5 Incidence of MPS in India ........................................................... 30 2.4.6 Birth Prevalence of MPS in Tunisia ............................................ 31 2.4.7 Birth Prevalence of MPS in Australia .......................................... 31 2.4.8 Birth Prevalence of MPS in British Columbia, Canada ............... 32 2.4.9 Birth Prevalence of MPS in Brazil ............................................... 33 2.4.10 Birth Prevalence of MPS in the Czech Republic ......................... 33 2.4.11 Birth Prevalence of MPS in Denmark, Norway, and Sweden ..... 34 vii 2.4.11.1.1 Denmark ...................................................... 34 2.4.11.1.2 Norway ........................................................ 34 2.4.11.1.3 Sweden ........................................................ 35 2.4.12 Birth Prevalence of MPS in Estonia ............................................ 35 2.4.13 Birth Prevalence of MPS in Germany ......................................... 36 2.4.14 Birth Prevalence of MPS in the Netherlands ............................... 37 2.4.15 Birth Prevalence of MPS in Northern Ireland .............................. 37 2.4.16 Birth Prevalence of MPS in Poland ............................................. 38 2.4.17 Birth Prevalence of MPS in Portugal ........................................... 39 2.4.18 Birth Prevalence of MPS I in the United States ........................... 39 2.4.18.1.1 State of Illinois ............................................ 40 2.4.18.1.2 State of Missouri ......................................... 40 2.4.18.1.3 University of Washington Study ................. 40 2.5 Discussion ................................................................................................ 41 DIAGNOSIS AND PROGNOSIS FOR MUCPOLYSACCHARIDOSIS IVA ........... 52 3.1 Clinical Diagnosis .................................................................................... 53 3.2 Clinical Diagnosis .................................................................................... 57 3.2.1 Urinary and Blood GAG .............................................................. 57 3.2.2 Keratan Sulfate (KS) .................................................................... 57 3.2.3 Chondroitin-6-sulfate (C6S) ........................................................ 61 3.2.4 Enzyme assay ............................................................................... 62 3.3 Radiographic diagnosis ............................................................................ 64 3.3.1 Skeletal
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