Natural History and Biomarkers of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Caused by the C9ORF72 Gene Mutation

Objective

The primary objective of this study is to characterize the natural history of disease in patients who carry a repeat expansion in the C9ORF72 gene, which causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The secondary objective is to assess whether candidate biomarkers correlate with disease progression.

Study population

62 persons with a documented repeat expansion in C9ORF72 gene who have ALS, ALS-FTD, or FTD or who are carriers of the gene mutation and have a symptomatic family member.

Design

Participants will undergo a structured battery of clinical and neuropsychological tests at enrollment and at three follow-up visits to NIH to assess disease severity. During these visits, physiological, imaging, blood, and CSF for testing of candidate biomarkers will be obtained. Between visits to NIH, assessments of functional status and cognition will be carried out by phone. Participants may be seen earlier than the scheduled follow-up visit or at home if phone assessments indicate clinical deterioration.

Outcome measures

There will be three primary outcome measures, for changes in three areas of function over the first six months. The primary measure of the severity of motor clinical function will be the ALS Functional rating scale-revised (ALSFRS-R). The primary measure of the severity of cognitive function will be changes in verbal fluency score. The primary measure of the severity of behavioral dysfunction will be the caregiver assessment of the fronto-behavioral index (FBI). Secondary clinical outcomes will be the forced vital capacity (FVC) and survival. The correlation between primary and secondary clinical outcome measures and candidate biomarkers measures will be analyzed in an exploratory fashion to determine whether candidate biomarkers are predictive of disease onset or progression.

• INCLUSION CRITERIA:

Patients will be included if they:

• Are age 18 or older
• Have a confirmed repeat expansion in the C9ORF72 gene

Exclusion criteria

Patients will be excluded if they

• have other major neurological or medical diseases that may cause progressive weakness or cognitive dysfunction, such as structural brain or spinal cord disease, metabolic diseases, paraneoplastic syndromes, hereditary diseases, infectious diseases, peripheral neuropathy or radiculopathy or other significant neurological abnormalities.
• require daytime ventilator support at the time of study entry
• are unable to travel to NIH at the time of study entry
• are unwilling to have follow-up visits
• are unable to understand or decline to sign the Informed Consent at the time of study entry. Participants can remain in the study (with DPA consent and participant assent) if they lose consent capacity.
• have pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, or shrapnel fragments, metal fragments in the eye) that exclude magnetic resonance imaging
• have unstable medical conditions that, in the opinion of the investigators, prevent safe participation in this study.
• are participating in experimental treatment trials at the time of study entry or plan such participation within 6 months of entry.

Patients will not be excluded if they are receiving standard care medications for treatment of ALS and its symptoms, or are participating in non-treatment clinical research studies. Patients will be permitted to participate in experimental treatment trials after the 6 month follow-up visit.

Patients with pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, or shrapnel fragments, metal fragments in the eye) will not be excluded but will not undergo magnetic resonance imaging or transcranial magnetic stimulation.