List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I MR imaging characteristics and neuropathology of the spin- al cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms. Sundblom J, Melberg A, Kalimo H, Smits A, Raininko R. AJNR Am J Neuroradiol. 2009 Feb;30(2):328-35. II Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms. Schuster J, Sundblom J, Thuresson AC, Hassin-Baer S, Klopstock T, Dichgans M, Cohen OS, Raininko R, Melberg A, Dahl N. Neurogenetics. 2011 Feb;12(1):65-72. III Bedside diagnosis of rippling muscle disease in CAV3 p.A46T mutation carriers. Sundblom J, Stålberg E, Osterdahl M, Rücker F, Montelius M, Kalimo H, Nennesmo I, Islander G, Smits A, Dahl N, Melberg A. Muscle Nerve. 2010 Jun;41(6):751-7. IV A family with discordance between Malignant hyperthermia susceptibility and Rippling muscle disease. Sundblom J, Mel- berg A, Rücker F, Smits A, Islander G. Manuscript submitted to Journal of Anesthesia. Reprints were made with permission from the respective publishers. Contents Introduction..................................................................................................11 Background and history............................................................................... 13 Early studies of hereditary disease...........................................................13 Darwin and Mendel................................................................................. 14 Mendel rediscovered: genetics evolving..................................................14 Eugenics: dark legacy..............................................................................15 Birth of molecular genetics......................................................................16 Human molecular genetics...................................................................... 17 Unfulfilled hopes?................................................................................... 17 Remarks on Medical Genetics......................................................................19 Neurogenetics.............................................................................................. 21 Clinical pointers...................................................................................... 21 Finding disease-causing mutations.......................................................... 22 Types of mutations.................................................................................. 23 Mechanisms affecting pathogenesis........................................................24 Treating neurogenetic disorders...............................................................25 Care and symptomatic relief............................................................... 25 Screening and monitoring................................................................... 25 Replacement/elimination therapy........................................................26 Medical treatment targeting the genetic machinery.............................26 Gene therapy....................................................................................... 27 Cell replacement technology...............................................................28 RNA silencing.....................................................................................28 Translational applications........................................................................ 29 Adult-onset autosomal dominant leukodystrophy with autonomic symptoms (ADLD)........................................................................................................30 Introduction............................................................................................. 30 Genetics...................................................................................................31 Clinical findings ..................................................................................... 31 Differential diagnosis.............................................................................. 32 Molecular mechanisms............................................................................ 35 Treatment options.................................................................................... 36 Rippling muscle disease............................................................................... 38 Introduction............................................................................................. 38 Malignant hyperthermia.......................................................................... 39 Genetics...................................................................................................39 Clinical findings...................................................................................... 40 Differential diagnosis.............................................................................. 41 Molecular mechanisms............................................................................ 42 Treatment options.................................................................................... 43 Aims.............................................................................................................44 Paper I..................................................................................................... 44 Paper II.................................................................................................... 44 Paper III...................................................................................................44 Paper IV.................................................................................................. 44 Methods....................................................................................................... 45 Paper I..................................................................................................... 45 Subjects...............................................................................................45 Magnetic resonance imaging (MRI)....................................................45 Histopathology....................................................................................46 Paper II.................................................................................................... 46 Subjects...............................................................................................46 Duplication analysis............................................................................46 Quantitative reverse transcriptase PCR (qRT-PCR) and western blot analyses of lamin B1 in nucleated blood cells.....................................46 Statistical analysis...............................................................................47 Paper III...................................................................................................47 Subjects...............................................................................................47 Neurophysiological studies................................................................. 48 Muscle pathology................................................................................48 Genetic analysis. ................................................................................ 49 Paper IV.................................................................................................. 49 Results......................................................................................................... 50 Paper I..................................................................................................... 50 Measurements of the spinal cord.........................................................50 Signal intensity of the spinal cord....................................................... 50 Histopathological findings.................................................................. 50 Paper II.................................................................................................... 51 Clinical and neuroradiological features...............................................51 Analysis of gene copy number variation (CNV).................................51 LMNB1 expression ............................................................................ 52 Paper III...................................................................................................52 Clinical investigation.......................................................................... 52 Neurophysiological studies................................................................. 53 Muscle pathology................................................................................53 Genetic analysis.................................................................................. 54 Paper IV.................................................................................................. 55 Discussion.................................................................................................... 56 ADLD......................................................................................................56 RMD........................................................................................................57 Sammanfattning........................................................................................... 59 Acknowledgements...................................................................................... 63 References....................................................................................................66