This thesis describes the clinical features of LGMD1D, a DNAJB6 mutated autosomal domi-nant LGMD disease, and introduces pathomechanisms of muscle chaperonopathies in general.
The term chaperonopathy refers to conditions where maintenance of protein integrity and sar-comeric structures by chaperonal systems is defect, including the autophagy pathways such as the CASA complex. The findings described here will help the clinicians to recognize the dis-ease based on typical clinical, MRI and myopathological findings that guide towards appro-priate molecular genetic analysis.
1. LGMD1D can be suspected on clinical grounds based on phenotype description.
2. Extensions of the base line phenotype do occur, both towards milder, later onset disease forms, and towards more severe, childhood-onset forms.
3. Muscle MRI findings are so characteristic in LGMD1D that they can lead directly to-wards molecular genetic testing.
4. Muscle biopsy findings confirm the early myofibrillar disintegration events starting in the Z-disc followed by autophagic secondary rimmed vacuolar pathology.
The exact characterization of the disease including the primary gene defect is the first step towards options for therapeutic interventions in order to reach a cure or significant slow-down of the disease progression.
Limitations of the study:
1. Prospective nature of the study; systematic approach of the patients not always possible.
2. Some patients lacking the follow-up; status at the moment representing one point at dis-ease duration timeline.
Acknowledgements
This study was conducted at Tampere University Hospital, Department of Neurology and Neuromuscular Research Center in 2008–2014. I thank all the patients who have participated in this project and their families.
I am sincerely grateful to Docents Päivi Hartikainen and Björn Falck for reviewing my thesis. Professor Kari Majamaa I thank cordially for doing me the honour of being the official opponent.
During the period of 2008–2014 research funding for the study was received from South Ostrobothnia Hospital District Research Fund and Tampere University Research Fund. I greatly appreciate their support that made this work possible. I also thank Professor Hannu Puolijoki, The Chief Medical Director of Seinäjoki Central Hospital, and Jaakko Pihlajamäki, Head of Hospital District, for positive atmosphere towards clinical research.
Like many big decisions in life the decision of making this thesis was not exactly planned. After years of busy clinical work I was longing to learn more about neuromuscular diseases but was short of time and chance to get expert level tutorial guidance. The project itself more like came to me; I contacted professor Udd about a chance to do some clinically relevant research, perhaps a single project. And indeed there was a good project available: a large family with muscular dystrophy without a definite diagnosis. From that point on things started to roll on, inevitably.
So I express my deepest gratitude to my supervisor, Professor Bjarne Udd for his untiring guidance and providing the greatest inspiration for clinically targeted neuromuscular research.
His teaching has made big difference in my approach to neuromuscular patients. His conta-gious enthusiasm towards neuromuscular research has been a source of strength not only to myself but also for many co-operating clinicians. It has been a privilege to enjoy world-class clinical guidance.
Docents Johanna Palmio and Aki Hietaharju are warmly thanked for agreeing to operate as a follow-up group for the research and providing valuable advice and support when needed.
I thank Tampere Neuromuscular research center team for their support, help and co-operation. Especially Sini Penttilä and Sanna Huovinen have provided invaluable help and support during my work. Olayinka Raheem, Tiina Suominen, Hannu Haapasalo and Manu Jokela have done excellent work in our mutual projects. I also thank all laborators and techni-cians in Neuromuscular Research Center lab for their impeccable work.
To neuromuscular research team at Folkhälsan Genetic Institute and Helsinki University I owe thanks for superior genetic and functional studies. Docent Peter Hackman, Helena Luque, Jaakko Sarparanta and Per-Harald Jonson have worked endless hours to achieve the unique results we have seen. Giorgio Tasca has been most helpful delivering MRI data and good companion in Neuromuscular Outpatient Clinic in Tampere University Hospital.
Docent Ibrahim Mahjneh is thanked for delivering important patient files and pedigree detail. He has been kindly interested in my work and followed it during the process.
This thesis and its side-projects have involved dozens of people; suffice it for me to say that I am grateful and proud to have worked with them all. It has been an enriching experi-ence.
This work would have been impossible to carry out without the support of my colleagues at Department of Neurology, Seinäjoki Central Hospital. Keijo Koivisto, Head of Department, is thanked for his research-friendly attitude. Lauri Herrala, Marianne Männikkö, Minna Raunio, Susanna Hintikka, Maire Rantala, Juha Sajanti and Maria Rantamäki have followed my work and shared some ups and downs of it. I thank all these hard-working people in gen-eral. Head of Department of Clinical Neurophysiology Hannu Heikkilä I want to thank for kind and supporting attitude towards my work and giving excellent neurophysiological points when needed. I also thank the whole staff at the Department of Clinical Neurophysiology and at Neurology Outpatient Clinic for showing interest towards my work. Sanna-Kaisa Toivak-ka-Hämäläinen at the Department of Radiology has given valuable advice and teaching re-garding soft tissue imaging by MRI, I thank her for that. I also thank my part-time workplace colleagues at Tampere University Hospital, Department of Neurology for stimulating conver-sations and inspiring collegial support. Sirpa Antonen receives special thanks for managing
the practical side of Neuromuscular Research Center Outpatient Clinic in especially kind and practical manner.
I also owe credit to my former employer, Neurology and Clinical Neurophysiology de-partment at Keski-Pohjanmaa Central Hospital, Kokkola. Victoria Ostrovska and Kirsi Juvila are thanked for their support and interest for my work. Former head of department, long-time friend of mine Sinikka Ingo I thank for good collaboration, excellent work ethics and some powerful mentoring.
Besides scientific work I thank Mrs. Taana Sandman for skillful secretarial work, graphics and layout planning, and kindly acting as an IT help desk when needed.
I thank my family and friends for their understanding and support, tolerating my absent-mindness and long working hours. I especially thank Minna Kivimäki for keeping medical issues in my head in some proportion, tolerating occasional whining, and providing the vo-cabulary advice, most often asked late at night by text message. All sports-related people in my life I thank for reminding me constantly that man does not function by intellect only.
Finally, I am grateful for my dear husband Seppo and our children Sampo and Panu for their love and support. Without them, none of this would have been possible.
Two roads diverged in a wood, and I took the one less traveled by.
And that has made all the difference.
Robert Frost (1874–1963)
Seinäjoki, March 2015
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