Antioxidant Therapy in RYR1-Related Congenital Myopathy

Summary

Background: \- Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common non-dystrophic muscle diseases that people are born with in the U.S. They affect development, muscles, and walking. Researchers want to test a new drug to help people with these diseases. Objectives: \- To see if the drug N-acetylcysteine decreases muscle damage in people with RYR1-RM. To see if it improves their exercise tolerance. Eligibility: \- People age 7 and older with a confirmed genetic diagnosis of RYR1 or a clinical diagnosis of RYR1 and a family member with a confirmed genetic diagnosis. Design: * Participants will be screened with a checklist of criteria. Adult participants may have a muscle biopsy. A needle will remove a tiny piece of muscle in the lower leg. * Study visits will take several days. * Visit 1: * Medical history * Physical exam * Blood, urine, and saliva tests * Questions about symptoms and quality of life * Heart, lung, and walking tests * Muscle Oxygenation Capacity Test. A blood pressure cuff around the thigh will be tightened for up to 10 minutes. * Biodex testing, stretching the leg against resistance * Muscle ultrasounds. A probe will be moved over the skin. * Participants may be photographed or videotaped during procedures. * They may have a muscle biopsy. * Six months later, visit 2 will repeat visit 1. Participants will start taking the study drug dissolved in water or placebo three times a day for 6 months. * Participants will stay at NIH for 2 days after starting the study drug. * Participants will be contacted by phone during the study to monitor side effects * Six months after starting the study drug, study visit 3 will repeat some or all of visit 1.

Timeline

Start

2015-02-12

Primary completion

2018-05-30

Completion

2018-05-30

Publications

• Chin LMK, Todd JJ, Chrismer IC, Witherspoon JW, Jain M, Waite M, Meilleur KG, Drinkard B, Lawal TA. Exercise capacity in RYR1-related myopathies. Orphanet J Rare Dis. 2025 Sep 24;20(1):485. doi: 10.1186/s13023-025-04013-7.
• Greer LK, Meilleur KG, Harvey BK, Wires ES. Identification of ER/SR resident proteins as biomarkers for ER/SR calcium depletion in skeletal muscle cells. Orphanet J Rare Dis. 2022 Jun 13;17(1):225. doi: 10.1186/s13023-022-02368-9.
• Todd JJ, Lawal TA, Witherspoon JW, Chrismer IC, Razaqyar MS, Punjabi M, Elliott JS, Tounkara F, Kuo A, Shelton MO, Allen C, Cosgrove MM, Linton M, Michael D, Jain MS, Waite M, Drinkard B, Wakim PG, Dowling JJ, Bonnemann CG, Emile-Backer M, Meilleur KG. Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies. Neurology. 2020 Mar 31;94(13):e1434-e1444. doi: 10.1212/WNL.0000000000008872. Epub 2020 Jan 15.
• Witherspoon JW, Vasavada RP, Waite MR, Shelton M, Chrismer IC, Wakim PG, Jain MS, Bonnemann CG, Meilleur KG. 6-minute walk test as a measure of disease progression and fatigability in a cohort of individuals with RYR1-related myopathies. Orphanet J Rare Dis. 2018 Jul 3;13(1):105. doi: 10.1186/s13023-018-0848-9.

Drugs

Indications