Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4 and Other Inherited Neurological Disorders of RNA Processing

Objective: Amyotrophic lateral sclerosis type 4 (ALS4) is an inherited form of motor neuron disease caused by mutation in the senataxin (SETX) gene. The main goal of this study will be to collect clinical and molecular biomarkers from patients with ALS4 to understand the natural history and progression of the disease. The biomarkers identified will serve as potential tools for the evaluation of efficacy in future therapeutic studies in ALS4. The protocol will primarily seek to enroll patients with mutation in the SETX gene and follow these individuals annually for 3 years. Individuals with mutation in genes that are predicted to result in a similar disruption of RNA processing (such as ribonuclease H1 and H2 (RNASEH1+2) genes and recessive mutations in SETX will serve as disease controls and participate in follow-up for 3 years to collect clinical and molecular biomarkers. ALS4 and disease control subjects who have had their mutation identified in protocol 00-N-0043 or protocol 12-N-0095, or those who have had previous genetic testing will be potential candidates for enrollment in this study. Healthy control populations (related, unaffected healthy controls and unrelated, healthy controls) will be screened for under this study and participate in a single visit to collect clinical and molecular biomarkers. Healthy control populations will participate in clinical and molecular biomarker collection for comparison to the ALS4 cohort. Related, unaffected healthy controls may also be screened under protocol 00-N-0043. No clinical genetic testing will take place under this protocol; however, research testing of genetic modifiers may be performed.

Study population: There will be a total of 315 subjects enrolled under this protocol. The protocol will seek to enroll up to 65 participants with mutation in SETX (ALS4) for annual follow-up, and up to 50 disease control participants with mutation in other genes which alter RNA processing (e.g., RNASEH1+2 and loss of function SETX mutations in patients with ataxia and oculomotor apraxia type 2[AOA2]). Up to 150 related, unaffected healthy relatives of the ALS4 and disease control groups may also be enrolled as controls. Additionally, a maximum of 50 unrelated healthy volunteers who are age and sex matched to the affected ALS4 and disease control participants will also be enrolled.

Study Design: Patients with ALS4 inherited defect in SETX will be evaluated at the NIH clinical center to characterize clinical features of the disease and collect clinical and molecular biomarkers. Disease controls will be evaluated to collect molecular biomarkers and clinical measurements at the discretion of the investigator. Patients with ALS4 and Disease Control participants will report to the NIH every 12 months (plus or minus 60 days) for clinical and molecular studies for a total of 4 visits. Healthy control populations (related, unaffected healthy controls and unrelated healthy controls) will be evaluated for a single visit to collect clinical and molecular biomarkers. An offsite visit, conducted in person at the participant s home, may be completed for the related, unaffected healthy control group, the disease control group, and in up to 15 ALS4 participants.

Outcome measures: No specific primary and secondary outcomes will be specified; however, the change in the following measures from baseline may be used to characterize the baseline status and disease progression over the course of the study: magnetic resonance imaging (MRI) evaluation of the lower extremity (muscle volume and fat fraction), dual-energy X-ray absorptiometry (DEXA) scan of whole body composition (lean body mass), quantitative muscle strength testing (QMT) of the upper and lower extremities, 6 minute timed walk test (6MTWT), timed up and go (TUG), 30 second chair stand test, pinch strength test, activity card sort (ACS), disabilities of the arm, shoulder, and hand (DASH), and the grooved pegboard test. Molecular biomarkers of RNA processing will be evaluated in the ALS4 group and control groups (healthy and disease) to identify those molecular biomarkers that are disease specific (disease vs. control) as well as those that are informative of disease progression in ALS4 (early vs. advanced disease). Clinical measurements of neuromuscular ultrasound, MRI, DEXA scan of whole body composition (lean body mass), QMT of the upper and lower extremities, 6MTWT, TUG, 30 second chair stand test, pinch strength, ACS, DASH, SF36 questionnaire, ALS Health Index (ALS-HI) questionnaire, Patient-Perceived Change in Function Question, and grooved pegboard test will provide a determination of disease severity in ALS4 patients and other inherited neurological disorders of RNA processing. The molecular biomarkers from ALS4 patients will be compared to the healthy control groups and the disease control group in order to determine which measurements are specific to the ALS4 disease.