The motivation and rationale for project 1 derives from the increasing recognition that ALS and related disorders represent syndromes with shared pathophysiological mechanisms, but a multitude of different (often genetic) causes. This realization is prompting an increasing interest in the ideas that one treatment may not be appropriate for all patients with each clinical syndrome, but rather that different therapeutic approaches might be needed depending on the underlying etiology of disease. It is against this background that defining the temporal course of disease and delineating the variability in rates of disease progression in genetically homogeneous patient populations has emerged as an essential stes in preparing for the future of clinical trials in ALS and related disorders. The principal goal of Project-1 of this RDCRC is to define the natural history (i.e. the temporal rate of disease progression) of disease in patients with ALS and related disorders who harbor different underlying genetic mutations;A secondary goal is to characterize the spatial and temporal patterns of disease progression within these individual disease categories, with a focus on ALS.
Successful completion of this project will shed significant light on the phenotypic correlates of genotype in ALS and related disorders, thereby empowering future therapeutic and disease prevention trials for patients with this group of neurodegenerative disorders in whom the underlying genetic etiology has been identified. These studies will also elucidate the pattern(s) with which disease progresses through the nervous system.
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|Esanov, Rustam; Belle, Kinsley C; van Blitterswijk, Marka et al. (2016) C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells. Exp Neurol 277:171-177|
|Rebelo, Adriana P; Abrams, Alexander J; Cottenie, Ellen et al. (2016) Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy. Am J Hum Genet 98:597-614|
|Rossor, Alexander M; Oates, Emily C; Salter, Hannah K et al. (2015) Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. Brain 138:293-310|
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