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.
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. ...
⁃ ALS4 RNA metabolism inclusion criteria:
• Age 5 or above
• Genetic diagnosis of ALS4 (heterozygous mutation in SETX)
• Able to communicate well with the investigator, to understand and comply with the requirements of the study
• Capacity to consent (adults) or assent (pediatric subjects) to the study
⁃ Disease control inclusion criteria:
• Age 5 or above
• Genetic diagnosis of RNA processing defect mutation (RNaseH1, RNaseH2, recessive mutations in SETX)
• Able to communicate well with the investigator, to understand and comply with the requirements of the study
• Capacity to consent (adults) or assent (pediatric subjects) to the study
⁃ Related, unaffected healthy control inclusion criteria:
• Age 5 or above
• Family history (first, second, or third degree relative) of RNA processing defect mutation (RNaseH1, RNaseH2, heterozygous or recessive mutations in SETX)
• Able to communicate well with the investigator, to understand and comply with the requirements of the study
• Capacity to consent (adults) or assent (pediatric subjects) to the study
⁃ Unrelated, healthy control inclusion criteria:
• Age 5 or above
• Able to communicate well with the investigator, to understand and comply with the requirements of the study
• Capacity to consent (adults) or assent (pediatric subjects) to the study
⁃ Gain of function inclusion criteria:
• Age 5 or above
• Genetic diagnosis of mutation resulting in a gain of function mechanism (for example, heterozygous mutations in SETX or heterozygous mutations in KCC3)
• Able to communicate well with the investigator, to understand and comply with the requirements of the studyCapacity to consent (adults) or assent (pediatric subjects) to the study
• Capacity to consent (adults) or assent (pediatric subjects) to the study