A Natural History Study of RYR1-Related Disorders

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:

• Investigate potential biomarkers of disease status and progression
• Explore clinical meaningfulness thresholds for research assessments
• Extract common data elements from existing medical records (real-world 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
• Dilated ophthalmology exam at baseline only
• Extraocular motility assessment
• Marginal reflex distance (Ptosis)
• Optical Coherence Tomography
• Ancillary testing, imaging, and repeat dilated exams as indicated, based on assessment and discretion of clinician

Secondary:

Change from baseline to Year 5 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
• Dilated ophthalmology exam at baseline only
• Extraocular motility assessment
• Marginal reflex distance (Ptosis)
• Optical Coherence Tomography
• Ancillary testing, imaging, and repeat dilated exams as indicated, based on assessment and discretion of clinician

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)

• INCLUSION CRITERIA (CENTRALIZED ARM)

• 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.
• Male or female, aged >=7 years of age.
• 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.
• Agreement to adhere to Lifestyle Considerations throughout study duration.
• 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.
• Resides in the United States.

Exclusion criteria

(CENTRALIZED ARM)

• Participation in an IND, IDE, or equivalent clinical study in the past six months
• Severe disability or mobility issues (inability to walk 10 meters with or without assistance)
• Requires mechanical ventilation or tracheotomy
• Other neuromuscular diseases resulting in muscle weakness
• 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.

Inclusion criteria

(DE-CENTRALIZED ARM)

• 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.
• Male or female, aged > 7 years of age.
• 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.
• 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.
• Resides in the United States

Exclusion criteria

(DE-CENTRALIZED ARM)

• Participation in an IND, IDE, or equivalent clinical study in the past six months
• Other neuromuscular diseases resulting in muscle weakness
• 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