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Université Pierre Et Marie Curie University of Khartoum Université Pierre et Marie Curie University of Khartoum Cerveau-Cognition-Comportement (ED3C) Institut du Cerveau et de la Moelle Epinière / Equipe Bases Moléculaires, Physiopathologie Et Traitement Des Maladies Neurodégénératives Hereditary spastic paraplegias: clinical spectrum in Sudan, further deciphering of the molecular bases of autosomal recessive forms and new genes emerging Par Liena ELBAGHIR OMER ELSAYED Thèse de doctorat de Neuroscience Dirigée par Dr. Giovanni STEVANIN, Professor. Ammar ELTAHIR AHMED Présentée et soutenue publiquement le 27 avril 2016, devant un jury composé de: Pr.LEGUERN, Eric, PU-PH Représentant de l’UPMC Pr.KLEBE, Stephan, PU-PH Rapporteur Pr.KOENIG, Michel, PU-PH Rapporteur Pr.BOESPFLUG-TANGUY, Odile, PU-PH Examinateur Pr.ELTAYEB IBRAHIM, Mutaser, PU Examinateur Pr.ELTAHIR AHMED, Ammar, PU-PH Co-directeur de thèse Dr.STEVANIN, Giovanni, DR Directeur Dedication To my parents, husband, kids. I II Acknowledgement I am grateful to the members of my thesis defense jury who have kindly accepted to read and assess my PhD manuscript. I would also like to express my sincere gratitude to my thesis directors Dr.Giovanni Stevanin and professor Ammar Eltahir Ahmed for kindly accepting to guide me throughout my journey in this challenging PhD project. They have been quite supportive at each step and have given me a great deal of independence which has allowed me to gain the required skills in project management and trouble shooting and be prepared for the next step. Dr.Giovanni Stevanin has struggled to get me the budget necessary for my experiments and has gently helped me at each step despite his rather busy schedule. I enjoyed much his humble friendly attitude despite his vast knowledge in our weekly discussions that we had in the last two months of my stay in France. Pr.Ammar Eltahir has kindly taken the burden of the neurophysiological investigations and opened his heart and clinic for all patients included in the cohort. He has been quite supportive and enthusiastic to help me by all means and efficiently contributed to the recruitment of new families. I would like to thanks Pr.Alexis Brice for accepting to collaborate and acquaint me in his team and even taking all the effort to come to Sudan to finalize the collaboration. My gratitude is great for Prof. Victor Patterson who has practically started the collaboration by introducing me to Pr.Brice. He has been extremely supportive and encouraging. All my appreciation is conduced to my mentors Pr.Muntaser Eltayeb Ibrahim and Pr.Mustafa Idris Elbashir who embraced and supported me from the beginning when the project was just an ambitious day dreaming. Our collaborating Sudanese clinicians are the corner stone in this research. The three lively neuropaediatricians (Dr.Inaam Gashey, Dr.Maha Elseed and Dr.Ahlam Hamed ), the humane Dr.Sarah Misbah, Pr.Mustafa Salih, Pr.Mohamed Nagib and his team, Dr. Hassab Elrasoul Siddig, Pr. Farooq Yasin and all the referring physicians, the radiologists, the ophthalmologists and the neurophysiologists all have contributed significantly to establish this project. My sincere gratitude is conducted to the Sudanese patients and their families who were as kind as a Sudanese can be expected. Prof. Alexandra Durr and Prof. Odile Boespflug-Tanguy (and her team especially Imen Dorboz) have not saved any effort to help me build my expertise in clinical neurogenetic and neuropaediatrics. Pr.Eric Leguern valuable tips with his sense of humour were priceless. Prof. Anjon Audhya team (USA) has kindly performed all the biochemical functional studies for the TFG protein and with the Parkinson team (Dr.Suzanne Lesage and her team) has yielded our successful reports so thanks to their efforts. The assistants of Alexis Brice team (Lydia Guennec, Marie-Luce Poupinel-Descambres and Antoine Guisier) have been professional and if not for the efforts of Lydia Guennec in my registration for the PhD I would have been unable to continue. The French embassy in Sudan and Campus France and the University of Khartoum provided me with the scholarship that has enabled me to come and do the PhD study in France. III My acknowledgement to the funding agents of the study: the France-Parkinson Association (to AB), the Agence Nationale de la Recherche (SPATAX-QUEST project, to GS), the Verum Foundation (to GS and AB), the Roger de Spoelberg Foundation (R12123DD, to AB), the French Academy of Sciences (to AB), the European Union (Neuromics projects, OMICS call, to AB) and the European Joint Programme - Neurodegenerative Disease Research (JPND-COURAGE-PD) project and Programme d’Investissement d’Avenir IHU-A-ICM (ANR-10-IAIHU-06). I would like to transmit my gratitude to team of the DNA and Cell bank (with special regards to the friendly Sylvie Forlani and Christelle Dussert), the laboratory and bioinformatics staff of the sequencing platform (ICM) in which we performed all the next generation techniques and the bioinformatic analysis, the platform P3S where we had the homozygosity mapping experiments performed with the help of Dr.Wassila Carpentier (who has done big efforts not only to explain and train but also has given me valuable tips for my thesis writing). Working with the team of Dr.Giovanni Stevanin has been a pleasure. They have become my second family. Professionally, Marie Coutelier and Christelle Tesson helped me in the first steps of my PhD and have been quite cooperative whenever I needed. The moments that I had with Marie were great and extremely pleasant. With Marie I discovered that Paris is truly described the city of light and because of that I stated to fall in love with the quiet lighted streets at night. The help that I have received from Mathilde Mairey with a beautiful smile and a comforting attitude of a friend cannot be described by words. Her efforts to help me in the last months of my PhD make me run out of expressions. Sawssan Ben Romdhan has been the support (with a friendly spirit) that I needed at a time when I was so desperate because of the accumulating work. Dr. Frédéric Darios and his professional group have helped and trained me on the basics of manipulations of cells and functional experiments. Special thanks are conducted to the nice Typhaine Esteves. Livia Parodi, Federica Barreca, Graziella Mongone and Paola have made me believe that Italians are all kind. The special memories, help, great laughter and the discussions I had with Khalid Hamid El-Hachimi, Livia Parodi, Celine Lustremant, Valérie Drouet, Claire Pujol, Claire Sopie Davoine, , Khadija Tahiri, Sara Morais, Oriane Trouillard, Annie Sittler, Remi Valter, Julien Branchu make me grateful to them and I feel sad and tearful when I imagine that we can’t be together anymore as we used to be. Special thanks to Claire Pujol for helping me with the final editing of the manuscript. She helped me at the critical moments of extreme fatigue and exhaustion with unforgettable friendship spirit. My team members in Sudan have been the scaffolding unit of all the work. Ashraf Kambalawy, Mahmoud Koko, Rayan Abubakar established the team with me and their professional attitude, hard working, highly committed and loyalty made me surmount all the obstacles. All the younger members of my team have worked extremely hard just to make our work successful without waiting for any reward and they have represented our team in conferences and workshops in a distinct way (Arwa Babai, Zulfa Mohamed, Hiba Malik, Israa Zuhair, Amal Salah, Ahmed Khalid, Elhami Abdalmuti, Lina Salah, Duaa Mustafa, Mayada Osama, Nabila Mohamed Hasan, Abdelhamid Mohamed and the two under-graduates Malka Osman and Eman Osama). Finally but most importantly, I would like to say honestly and proudly say that if not for the support of my family I would have done literally nothing. They have set an example of a great family who would sacrifice for the sake of others. My husband I would describe as a great man. Not only has he sacrificed all his rights of a stable situation with a settled wife but also IV he supported me psychologically and financially. My parents ElBaghir Omer Elsayed and Fatma Elsaraj have taken care of my kids and I would say my mother deserves a medal of honour for taking in charge the responsibilities of my kids’ studies and have made them brilliant youngsters better than what I could have done. My kids (Tull, Abdelaziz and Yusr) have encouraged me to go on when I was in despair and they insisted that I continue to help the patients. My parents in law (Abdelaziz Tangasawi and Asia Abdallah) took in charge a significant deal of my responsibly towards my husband and kids in parenting manner. The precious professional advices of my father in law have been extremely useful. My brother Omer Elbaghir has shown me what it means to be a brother. He supported me psychologically and supported my research financially with real love. His wife Dina Saklah used to call me to encourage me. I would like to thank all my dear sisters (Lubaba, Lubna and Shayamaa) and their families for the continuous supporting love. All my appreciation Shaymaa who helped my mother in her care for my kids in silent way. Finally, my thanks are to other friends and family that I could not list all. The combined efforts of everyone have helped me overcome the sorrow that I used to experience upon separation from my family over long months I spent alone in France. Liena Elbaghir Omer Elsayed University of Khartoum/University of Paris 6 February 2016 V I Table of Contents Introduction 1. State of the art 1 1.1. Clinical spectrum of HSP 3 1.1.1. Associated signs and clinical phenotypes 3 1.1.2.
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