A 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), stratified into centralized (ambulatory) and decentralized (non-ambulatory) arms. 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:

Characterize phenotype and disease course over a three-year period

Secondary:

Characterize phenotype and disease course over an extended (2-year) period (total 5 years)

Exploratory:

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:

   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)
   * Performance of Upper Limb (PUL)
   * 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 (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 (subscale and overall t-scores); 8 - 17 y
   * PROMIS Parent Proxy 25 Profile - Fatigue, physical stress experiences, positive affect and wellbeing, psychological stress experiences, anxiety/fear, physical function, pain; 5 - 7 y
   * PROMIS Upper Extremity - Short Form 7a
   * PROMIS Pediatric Upper Extremity - Short Form 8a
   * PROMIS Parent Proxy Upper Extremity - Short Form 8a
   * 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

   Ophthalmology
   * Visual acuity
   * Extraocular muscle excursions photography
   * 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

   Exploratory:

   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
   * PBMC (Peripheral Blood Mononuclear Cell)
   * Near infrared spectroscopy (muscle tissue oxygenation)
   * Dixon MRI of lower extremity
   * Optional skin punch biopsy (fibroblast culture)
   * Muscle ultrasound
   * Electrical impedance myography (EIM)

Eligibility Criteria:
* INCLUSION CRITERIA (CENTRALIZED ARM)

  1. Stated willingness to comply with all study procedures, availability for the duration of the study, and submission of medical records to research team prior to screening.
  2. Male or female, aged \>=7 years of age.
  3. Genetically confirmed RYR1-related disorder, evidenced by pathogenic or likely pathogenic variants identified by CLIA testing (whole genome, exome, targeted, partial or full RYR1 sequencing) OR variant of uncertain significance with supporting clinical phenotype.
  4. Agreement to adhere to Lifestyle Considerations throughout study duration.
  5. Ability of subject to communicate their understanding of the purpose of the study, and willingness to provide assent and/or to sign a written informed consent document.
  6. Resides in the United States.

INCLUSION CRITERIA (DE-CENTRALIZED ARM)

1. Stated willingness to comply with all study procedures, availability for the duration of the study, and submission of medical records to research team prior to screening.
2. Male or female, aged \> 7 years of age.
3. Genetically confirmed RYR1-related disorder, evidenced by pathogenic or likely pathogenic variants identified by CLIA testing (whole genome, exome, targeted, partial or full RYR1 sequencing) OR variant of uncertain significance with supporting clinical phenotype.
4. Ability of subject to communicate their understanding of the purpose of the study, and willingness to provide assent and/or sign a written informed consent document.
5. Resides in the United States

EXCLUSION CRITERIA (CENTRALIZED ARM)

1. Participation in an IND, IDE, or equivalent clinical study in the past six months
2. Severe disability or mobility issues (inability to walk 10 meters with or without assistance)
3. Requires mechanical ventilation or tracheotomy
4. Other neuromuscular diseases resulting in muscle weakness
5. Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study (e.g. active infection) or safety of the subject.

EXCLUSION CRITERIA (DE-CENTRALIZED ARM)

1. Participation in an IND, IDE, or equivalent clinical study in the past six months
2. Other neuromuscular diseases resulting in muscle weakness
3. Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study (e.g. active infection) or safety of the subject