An Observational Study to Assess Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4, Other Inherited Neurological Disorders With RNA Processing Defects, and Other Neurological Diseases With a Gain of Function Mechanism.
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 330
- 试验地点
- 1
- 主要终点
- Disease progression as measured by thigh muscle volume and other study measures
研究概览
简要总结
Background:
Amyotrophic lateral sclerosis type 4 (ALS4) is an inherited motor neuron disease. People with ALS4 have a change in the amount of RNA and DNA that bind together. This binding of RNA with DNA forms units called R-loops. Researchers want to learn how R-loops are related to ALS4. To do this, they will study people with inherited neurological conditions that may affect R-loop levels. These include ALS4, progressive external opthalmoplegia with mitochondrial deletions (PEOB2), Aicardi-Goutieres syndrome (AGS), and ataxia and oculomotor apraxia type 2 (AOA2).
Objective:
To learn how the binding of RNA with DNA (R-loops) is related to neurological disease.
Eligibility:
People age 5 and older with ALS4, PEOB2, AGS, and AOA2. Healthy relatives and nonrelatives are also needed.
Design:
Participants may be screened with a review of x-rays and other medical records.
Healthy relative and nonrelative participants will have 1 visit. All other participants will have 4 visits over 3 years.
At visits, participants will undergo some or all of the following:
Medical history
Physical exam
Tests of muscle strength and volume and physical function
Blood tests
Pregnancy test (for some females)
Skin biopsy of forearm
Magnetic resonance imaging (MRI)
Dual x-ray absorptiometry (DEXA).
Some tests are optional.
The MRI uses a magnetic field and radio waves to take pictures. Participants will lie on a table that slides in and out of the scanner. The scanner makes noise. They will get earplugs.
The DEXA scan uses x-rays to take pictures.
MRI and DEXA will be used to measure muscle, fat, and lean body mass.
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详细描述
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:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 5 Years 至 120 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
结局指标
主要结局
Disease progression as measured by thigh muscle volume and other study measures
时间窗: Baseline and annually at visits 2 - 4
Clinical and molecular measurements in ALS4 patients and other inherited neurological disorders of RNA processing will be assessed over the course of the study.
次要结局
未报告次要终点