4 型肌萎缩侧索硬化症和其他遗传性 RNA 加工神经系统疾病的临床表现和生物标志物

Objective:

Amyotrophic lateral sclerosis type 4 (ALS4) is an inherited form of motor neuron disease caused by a gain of function mutation in the senataxin (SETX) gene. The main goal of this study will be to collect clinical and molecular biomarkers from patients with ALS4 and other neurological diseases that have a gain of function mechanism to understand the natural history and progression of these diseases. The biomarkers identified will serve as potential tools for the evaluation of efficacy in future therapeutic studies in ALS4 and other neurological diseases that have a gain of function mechanism.

For the Inherited Forms of RNA Metabolism cohort, patients with mutation in the SETX gene (ALS4 RNA Metabolism patients) will be enrolled and followed 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 all ALS4 patients in study. 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.

For the Gain of Function cohort, patients with gain of function mutations in genes that result in other forms of neurological disease, as well as select patients with mutation in the SETX gene (select ALS4 patients), will be enrolled and followed annually for 5 years. Subjects in the Gain of Function cohort 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. No clinical genetic testing, such as whole genome or whole exome sequencing, will take place under this protocol; however, research testing of genetic modifiers may be performed. An additional goal of this study is to share clinical and molecular measures which are sensitive at detecting disease progression with collaborators working to develop therapeutics in patients with other forms of neurological disease caused by gain of function mechanisms.

Study population:

There will be a total of 330 subjects enrolled under this protocol.

For the Inherited Forms of RNA Metabolism cohort, up to 65 participants with mutation in SETX (ALS4 RNA Metabolism patients) will be enrolled 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]) will be enrolled. Up to 150 related, unaffected healthy relatives of the ALS4 RNA Metabolism patients and disease control group may also be enrolled as controls. Additionally, a maximum of 50 unrelated healthy volunteers who are age and sex matched to the affected ALS4 RNA Metabolism patients and disease control participants will also be enrolled.

For the Gain of Function cohort, up to 15 patients with gain of function mutations in genes that result in neurological disease (including select ALS4 patients) will be enrolled.

Study Design:

For the Inherited Forms of RNA Metabolism cohort, patients with ALS4 inherited defect in SETX (ALS4 RNA Metabolism patients) 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. ALS4 RNA Metabolism patients and Disease Control participants will report to the NIH every 12 months ( 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 RNA Metabolism participants in the Inherited Forms of RNA Metabolism cohort.

For the Gain of Function cohort, patients with gain of function mutations and neurological disease (including select SETX/ALS4 patients) will be evaluated at the NIH clinical center for a time period up to 5 years at a frequency determined by the discretion of the investigator, but no more frequent than every 6 months, for a total of up to 11 visits. Participants in the Gain of Function cohort will not be seen offsite.

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 and disease severity over the course of the study.

For both the Inherited Forms of RNA Metabolism cohort and the Gain of Function cohort: neuromuscular ultrasound, 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), SF36 questionnaire, ALS Health Index (ALS-HI) questionnaire, Patient-Perceived Change in Function Question, Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5), and the grooved pegboard test.

Molecular biomarkers will be evaluated in ALS4 patients (from both the Inherited Forms of RNA metabolism cohort and the Gain of Function cohort) and in the control groups (healthy and disease) (from the Inherited Forms of RNA metabolism cohort) 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).

For the Gain of Function cohort, the following additional measures may be used: revised upper limb module (RULM); Myotools assessment; 32 item motor function measure (MFM32); 9-hole peg test; Charcot-Marie-Tooth functional outcome measure (CMT-FOS); nerve conduction studies; electrical impedence myography (EIM); and accelerometry assessment.