The C9ORF72 GGGGCC repeat expansion associated with familial and sporadic amyotrophic lateral sclerosis (c9ALS), frontotemporal lobar degeneration with TDP-43 inclusions (c9FTD) and combined presentations of ALS with frontotemporal dementia (c9FTD/ALS) is the most common cause of familial ALS, ALS-FTD and FTD identified to date, and is reported in about 6% of sporadic ALS and FTD. The causes of phenotypic variability in c9ALS are not established. Wide ranging clinical expression of c9ALS is a challenge to elucidating the pathogenesis of the repeat expansion, as genotype-phenotype correlation calls for molecular genetic data and correlative clinical data in manifesting carriers of the repeat expansion and asymptomatic mutation carriers. Similarly, studies of disease pathogenesis using patient-derived biospecimens, including skin fibroblasts and assessment of postmortem neuropathology, require detailed clinical phenotypic data in order to associate biospecimen-derived data with clinical expression of disease. Studies in this P01 to elucidate the molecular pathogenesis of c9ALS will require ascertainment of patients with c9ALS, their extended family members who carry the C9ORF72 repeat expansion, and appropriate comparison groups with collection of clinical data, biospecimens and post mortem tissue. In order to identify symptomatic and asymptomatic C9ORF72 repeat expansion carriers for collection of longitudinal clinical data and biospecimens for Project 1, to provide clinical data and biospecimens of c9ALS and ALS patients with normal C9ORF72 repeat length for in vitro studies of disease mechanisms in Project 2, and to provide clinical data and post mortem tissue for investigation of the neuropathology of c9ALS in Project 3 the goals of Core B are: to identify for Project 1 at least 50 probands with c9ALS, and at least 10 ALS patients with normal C9ORF72 repeat length (c9(-)ALS) (Aim 1);through genealogic studies of c9ALS probands and c9(-)ALS patients ascertained in Aim 1 identify for Project 1 the following 3 categories of first, second and third degree blood relatives without symptoms of ALS or dementia: 1) at least 50 c9ALS relatives carrying the C9ORF72 repeat expansion;2) at least 5 c9ALS blood relatives who do not carry the repeat expansion;and 3) at least 5 blood relatives of c9(-)ALS patients (Aim 2);collect as called for in Project 2 single time point biospecimens including skin tissue from 1) at least 10 patients with c9ALS and 2) at least 10 c9(-)ALS patients ascertained through Aim 1 (Aim 3);and, offer all study subjects participation in our deeded autopsy program, and for those who die during the course of the project, conduct autopsies to harvest brain, spinal cord and other tissues in support of Projects 1 and 3.
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