The DIALS (Dominant Inherited ALS) Network

Overall Aim: Establish a multicenter research platform to evaluate people at high risk for ALS to identify early diagnostic signs and characterize biomarkers at the time of symptom conversion.

This project aims to establish a mechanism for genetic testing and research involvement of people at risk for inherited forms of ALS.

Aim 1: Provide a platform for the testing of known ALS causative genes in people at risk for familial ALS.

Substantial barriers prevent the development of a cohort of asymptomatic ALS gene carriers, including the cost and availability of genetic testing and counseling, and insurance risks of putting genetic information into the clinical chart. This study will break down these barriers by using a funded research platform to perform CLIA-certified genetic testing at the New York Genome Center (NYGC) and develop a standardized approach to genetic counseling in ALS.

Hypothesis: Establishing a cohort of asymptomatic ALS gene carriers will provide the opportunity to target people in the early stages of ALS to maximize treatment effects, similar to other neurodegenerative diseases (6).

Aim 2: Perform longitudinal evaluation of people at risk for inherited forms of ALS in order to identify biomarkers of disease initiation (i.e. molecular, electrophysiologic) and novel measures of clinical disease onset (i.e. ATLIS, IOPI).

Upon development of an asymptomatic gene carrier cohort, this study will routinely characterize these patients with leading ALS biomarker candidates and quantitative clinical outcomes to provide a means to identify disease onset earlier than ever before. Biomarker evaluation will include blood and optional CSF collection. Specifically, this project will evaluate the following candidate biomarkers: CSF SOD1, repeat-associated non-ATG (RAN) dipeptides in C9ORF72, phosphorylated neurofilament heavy (pNfH) and neurofilament light (NfL) chain.

Hypothesis: Longitudinal evaluation of asymptomatic ALS gene carriers will provide critical insight into the earliest clinical and biological changes associated with ALS, to facilitate early diagnosis and better define disease conversion in ALS. Comparison of candidate biomarkers in asymptomatic ALS gene carriers to biobanked specimens from existing protocols of symptomatic people with sporadic and familial ALS and healthy controls will help to characterize the earliest biomarker in ALS.

This study is looking to enroll about 55 asymptomatic first-degree relatives of known C9ORF72 and SOD1-positive patients with ALS from 2 ALS centers in the US. Study participants will be followed for 5 years regardless of gene status, with gene-negative participants providing important comparative information for leading candidate biomarker and outcome development. Study visits for collection of clinical data and biofluid biomarkers will occur every 6 months from screening.

During the informed consent process, study participants will indicate preference to learn the results of genetic testing (i.e. disclosure group). It is anticipated that at least 70% (28 out of 40) of study participants who undergo genetic testing will opt for gene disclosure, based on prior research initiatives with disclosure and non-disclosure groups in asymptomatic ALS gene carriers. Study participants will undergo genetic counseling with medically-licensed study staff (physician site investigator or genetic counselor) as a part of disclosure group determination, to ensure participants are fully informed of the risk of life and long-term care insurance denial if a positive genetic result is known to them.

During the informed consent process, participants within the disclosure group will have the option to identify a designee to receive the study participant’s genetic results should the participant become unexpectedly incapacitated or pass away from a medical condition other than ALS. The designee will be an adult (i.e. over the age of 18) who is related to or known to the subject. Identification of a designee will be made in conjunction with genetic counseling with medically licensed study staff (physician site investigator or genetic counselor). By indicating preference for non-disclosure, genetic results will not be returned to the study participant or a designee. Individuals who initially elect non-disclosure can decide later to undergo genetic counseling and learn their genetic results at any time. Upon electing for disclosure, participants may then identify a designee to receive the study participant’s genetic results should the participant become incapacitated or pass away.