Understanding Clinical Phenotype and Collecting Biomarker Samples in C9ORF72 ALS

Design:
A series of in-person study visits will occur every 3-4 months for up to 3 years and include two, optional lumbar puncture visits for the collection of cerebral spinal fluid. For participants living in the local vicinity of one of our research centers, the in-person visits may be tied to a regular clinic visit. For out-of-town participants wishing to travel to a research center, please contact the center to determine if an initial, in-person visit may be scheduled and subsequent study visits performed via a telephone call and medical records review.

During the initial study visit, participants will be asked questions about their general health history and medical history/events; family history of diseases; medications being taken. In addition, the following will be performed: brief neurological and physical examination; completion of measures of disease progression including the revised ALS Functional Rating Scale (ALSFRS-R); Current breathing capacity (SVC/FVC); Brief Cognitive Behavioral Screen and Caregiver Behavioral Questionnaire (ALS-CBS); and blood sample donation for biomarker analysis.
Subsequent study visits, where similar information will be re-collected, will occur approximately every 3 months and can be scheduled around your regular clinic visit.

For out of town subjects who are enrolled into the project, serial blood collections may be scheduled locally and sent to the study site for analysis. In addition, the ALSFRS-R may be performed over the phone along with other study related questions about current medication, physical health and medical history/events that may have occurred since the previous study visit.

Background and Rationale for Study: The C9ORF72 mutation is called a "dominant" mutation, which means that their children have a 50% chance of inheriting the gene. Most people who inherit the C9ORF72 mutation will develop either ALS or the related disease called fronto-temporal dementia. However, it may be possible for someone to test positive for the C9ORF72 gene mutation and never develop symptoms. Furthermore, in addition to C9ORF72, there are many other gene mutations that can cause ALS. This study will not test these other genes, and therefore a negative test result for the C9ORF72 mutation will not exclude the possibility that you have a heritable form of ALS.

C9ORF72 repeat expansions were recently identified as a surprisingly common cause of ALS (30% of familial and 5-10% of sporadic ALS). Data collected to date suggest a toxic gain-of-function mechanism for the cause of neuronal loss, either by creating RNA-foci that sequester important RNA binding proteins or by translation of the repeat expansion into aggregation-prone dipeptides. This fact makes antisense oligonucleotide knock-down of C9ORF72 repeat RNA an attractive therapeutic strategy, which is already under development by several groups. Given a recently completed Phase I trial using antisense oligos (ASOs) targeted to SOD1, it is highly likely that a similar strategy will emerge for C9ORF72 in the near future. However, our understanding of clinical characteristics and effect of the hexanucleotide repeat expansion size for C9ORF72 are not yet ready for such a clinical trial. Our collaborative effort proposed here will generate these important phenotype/genotype correlations.

By determining the natural history of disease progression and the effect of the expansion size in patients with C9ORF72 expansions, we will be able to answer important questions regarding clinical trial design such as how many patients will be needed to see an effect on disease progression, whether there are geographic clusters of patients, and will establish an important historical control set that may be used in early clinical trials to determine whether there might be an effect on disease progression.

Minimum Age:

18 Years

Maximum Age:

N/A

Can participants use Riluzole?

Yes