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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2015 by National Institutes of Health Clinical Center (CC)
National Institute on Aging (NIA)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ) Identifier:
First received: August 15, 2013
Last updated: April 10, 2015
Last verified: March 2015


- Some people have a mutation in the C9ORF72 gene that causes amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). The mutation causes a small piece of DNA to repeat itself thousands of times. The C9ORF gene mutation mostly occurs in families. In those families, some persons have ALS and others have FTD. Occasionally the C9ORF gene mutation occurs in persons without a family history. Researchers want to understand how this gene causes different diseases. They will study how symptoms caused by the C9ORF gene develop and change over time. They will measure symptoms that occur in ALS and in FTD. In particular, they will measure strength, ability to move, thinking, and memory. They will also see if other tests are associated with progression of disease. These tests, called biomarkers, may help detect or measure C9ORF72 disease in the future.


- To understand how symptoms change over time in people with mutations in a gene called C9ORF72, which causes ALS and FTD.


- Adults over age 18 who have this genetic mutation


  • Participants will have up to 4 in-person visits and 3 telephone interviews over 3 years. Each in-person visit may take place over several days. They may be either inpatient or outpatient visits.
  • At each visit, participants will undergo a series of brain, language, and behavior tests. These will include:
  • Magnetic resonance imaging (MRI) of the brain. This uses magnets, radio waves, and computers to produce detailed pictures of the brain.
  • Collecting spinal fluid. The clinician will make the participant s back numb and then insert a needle to collect fluid.

< TAB> - Blood samples will be taken.

< TAB> - Participants will be asked to perform several language and movement tests.

< TAB> - Small skin samples will be taken on one visit

- Between visits, participants will answer questions about their health over the phone 3 times.

Amyotrophic Lateral Sclerosis

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: Natural History and Biomarkers of C9ORF72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • ALS Functional Rating Scale-revised [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Frontobehavioral Index [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Verbal Fluency Score [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 62
Study Start Date: August 2013
Estimated Study Completion Date: September 2018
Estimated Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)
Detailed Description:


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.


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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Patients will be included if they:

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


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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01925196

Contact: Carol H Hoffman (301) 496-7428
Contact: Mary Kay Floeter, M.D. (301) 496-7428

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010   
Sponsors and Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute on Aging (NIA)
Principal Investigator: Mary Kay Floeter, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
  More Information

Additional Information:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ) Identifier: NCT01925196     History of Changes
Other Study ID Numbers: 130188, 13-N-0188
Study First Received: August 15, 2013
Last Updated: April 10, 2015
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Motor Neuron Disease
Frontotemporal Dementia
Cognitive Testing

Additional relevant MeSH terms:
Amyotrophic Lateral Sclerosis
Aphasia, Primary Progressive
Frontotemporal Dementia
Motor Neuron Disease
Pick Disease of the Brain
Brain Diseases
Central Nervous System Diseases
Communication Disorders
Delirium, Dementia, Amnestic, Cognitive Disorders
Frontotemporal Lobar Degeneration
Language Disorders
Mental Disorders
Metabolic Diseases
Nervous System Diseases
Neurobehavioral Manifestations
Neurodegenerative Diseases
Neurologic Manifestations
Neuromuscular Diseases
Pathologic Processes
Proteostasis Deficiencies
Signs and Symptoms
Speech Disorders
Spinal Cord Diseases
TDP-43 Proteinopathies processed this record on November 24, 2015