Clinical Trial: Antioxidant Therapy in RYR1-Related Congenital Myopathy

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Antioxidant Therapy in RYR1-Related Congenital Myopathy

Brief Summary:

Background:

- Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common 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. They will 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 video
  

  Detailed Summary:

  Although genetic disorders of muscle that present at birth are rare, RYR1-related myopathies comprise the most common non-dystrophic congenital myopathy in the United States, with a prevalence of approximately 1/90,000 people (Amburgey et al, 2011). Causative mutations in the ryanodine receptor gene of skeletal muscle, RYR1, have been found in several myopathy subtypes, including central core disease and centronuclear myopathy. These mutations result in defective excitation-contraction coupling and increased mitochondrial oxidative stress. Most patients present in childhood with delayed motor milestones, extremity muscle weakness, impaired ambulation, joint contractures, progressive scoliosis, and in some cases eye movement paralysis, respiratory failure, or susceptibility to malignant hyperthermia, an allelic condition. Despite these important morbidities and the risk of early mortality, no treatments exist to date.

  RYR1 encodes a homotetrameric transmembrane ion channel, RyR1, which resides on the terminal sarcoplasmic reticulum in close proximity to the T-tubule. By releasing calcium from the sarcoplasmic reticulum into the cytosol in response to muscle fiber stimulation by the motor neuron at the neuromuscular junction, it mediates excitation-contraction coupling and functions as a regulator of cellular calcium concentrations and redox homeostasis. Dowling et al. (2012) recently elucidated the latter mechanism in zebrafish and patient myotubes, showing that RYR1 mutations result in increased oxidative stress and that this is rescued in both models by treatment with N-acetylcysteine (NAC), a known anti-oxidant. NAC functions as a precursor of glutathione, an endogenous antioxidant that becomes deficient during oxidative stress. This was substantiated by a cystic fibrosis clinical trial in which low glutathione levels in neutrophils undergoing oxidative stress significa
  Sponsor: National Institute of Nursing Research (NINR)
  

  Current Primary Outcome: Blood glutathione level [ Time Frame: 0, 6, 12 months ]
  
  

  Original Primary Outcome: Same as current
  
  

  Current Secondary Outcome: 6 minute walk test [ Time Frame: 0, 6, 12 months ]
  
  

  Original Secondary Outcome: Same as current
  
  Information By: National Institutes of Health Clinical Center (CC)
  

  Dates:
  Date Received: February 12, 2015
  Date Started: January 21, 2015
  Date Completion: December 18, 2017
  Last Updated: April 20, 2017
  Last Verified: February 28, 2017