Ryanodine Receptor 1 Related Disorders Clinical Trial
Official title:
A Single-Center Prospective Natural History Study of RYR1-Related Disorders
Background: Congenital myopathies (CM) are genetic disorders that can cause decreased muscle tone and muscle weakness. Most CMs in the United States are related to the ryanodine receptor 1 (RYR1) gene. Researchers need more natural history data to learn about these CMs in children and adults. Objective: To learn more about the signs, symptoms, and course of RYR1-related disorders. Eligibility: People aged 7 years and older with an RYR1-related disorder. Design: Ambulatory participants will come to the Clinical Center and non-ambulatory participants will visit via telehealth. Visits will be once a year for 3 or 5 years. Clinical Center visits will take 2 to 3 days. All participants will undergo tests including: Photos and videos. These will be taken to document the participant s condition. Blood and urine tests. Activity Tracker. Participants will wear a device to record their activity. Questionnaires. Participants will answer questions about their health, pain, fatigue, stress, quality of life, and other topics. Participants who visit the Clinical Center will also undergo: Tests of heart and lung function. Motor skills and strength tests. Participants will walk, climb stairs, kneel, crawl, stand up, and perform other movements to test their strength and abilities. They will squeeze and pinch a handheld device to test their grip. Imaging scans. Skin biopsy. Adult participants may opt to have a sample of skin taken (one time only). Eye exam
STUDY DESCRIPTION: This prospective natural history study seeks to characterize the clinical manifestations and course of Ryanodine Receptor 1 -related disorders (RYR1-RD). RYR1-RD include a wide range of rare congenital and adult-onset neuromuscular phenotypes that are typically slowly progressive. The study is observational and comprises a primary data collection phase (Years 1-3) and extended follow-up phase (Years 4-5). During each phase, there will be one visit per year. The study will enhance the foundational knowledge of RYR1-RD and support clinical trial readiness. OBJECTIVE: Primary Objective: Characterize phenotype and disease course over a three-year period Secondary Objectives: Characterize phenotype and disease course over an extended (2-year) period (total 5 years) Exploratory Objectives: 1. Investigate potential biomarkers of disease status and progression 2. Explore clinical meaningfulness thresholds for research assessments 3. Extract common data elements from existing medical records (realworld evidence) ENDPOINTS: Primary Endpoints: Change from baseline to Year 3 in: Motor function and performance - Motor Function Measure (MFM) sub-domains (percent of maximum score) - Six-minute walk test (meters travelled with percent predicted) - Timed functional tests (ascend four stairs, descend four stairs, supine to stand) (seconds) - Grip and pinch strength (kg and percent predicted) - Accelerometry (wearable sensor) - Quantitative muscle assessment - Brooke and Vignos assessment Pulmonary function - Forced vital capacity (percent reference norm) - Forced expiratory volume at 1 second (percent reference norm) - Slow vital capacity (Liters) - Maximal voluntary ventilation (Liters) - Maximum inspiratory pressure (MIP) - Maximum expiratory pressure (MEP) Patient-reported outcomes - PROMIS-57 Profile v2.1 (subscale and overall t-scores); adults - depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and satisfaction with participation in social roles - PROMIS Ped-25 Profile v2.0 (subscale and overall t-scores); 8 - 17 y - PROMIS Parent Proxy CAT v2.0 - Fatigue, physical stress experiences, positive affect and wellbeing, psychological stress experiences, anxiety/fear, physical function, pain; 5-7 y - NeuroQoL Upper and lower limb function - Physical Activity Questionnaire for Children (PAQ-C); 8 - 13 y - Physical Activity Questionnaire for Adolescents (PAQ-A); 14 - 17 y - International physical activity questionnaire (IPAQ); adults - Falls questionnaire; adults Ophthalmology - Marginal reflex distance (Ptosis) - Binocular horizontal visual field test - Optical Coherence Tomography - Goldmann Perimetry Degrees: lateral rectus, superior rectus, inferior oblique, medial rectus, superior oblique, inferior rectus Medical data review - Demographics - Developmental history - Medical history - Social determinants of health (environmental conditions such as economic stability, health care and education access and quality, neighborhood and built environment, and social and community context. - Full physical exam - Review of genetic diagnostic report/results - Prior medical records Adverse and disease-related events Serious (21CFR312.32) adverse events: - Narrative description (clinician) - Causality assessment (related or unrelated to disease) - CTCAE system organ class - CTCAE lower-level term Exploratory Endpoints: Biomarkers Including but not limited to: - Plasma NAD plus, NADH - Plasma GSH, GSSG - Plasma cytokines - Serum creatine phosphokinase - Urine and plasma 15-F2t isoprostane - Urine 8OHdG - Near infrared spectroscopy (muscle tissue oxygenation) - Dixon MRI of lower extremity - Optional skin punch biopsy (fibroblast culture) - Muscle ultrasound - Electrical impedance myography (EIM) ;