Rycal S48168 (ARM210) for -related myopathies: a phase one, open-label, dose-escalation trial.

Background: -related myopathies (-RM) are caused by pathogenic variants in the gene which encodes the type 1 ryanodine receptor (RyR1). RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to -RM pathogenesis.

Ryanodine Receptor 1-Related Myopathies: Quantification of Intramuscular Fatty Infiltration from T1-Weighted MRI.

Background: Ryanodine receptor 1-related myopathy (RYR1-RM) can present with a selective pattern and gradient of intramuscular fatty infiltration (IMFI) on magnetic resonance imaging (MRI).

Objective: To demonstrate an automated protocol for quantification of IMFI in the lower extremity muscles of individuals with RYR1-RM using T1-weighted MRI and to examine the relationships of IMFI with motor function and clinical severity.

Methods: Axial images of the lower extremity muscles were acquired by T1-weighted fast spin-echo and short tau inversion recovery (STIR) sequences.

Development of a proxy-reported scale to assess motor function in infants and young children with early-onset neuromuscular disorders.

Aim: To develop a novel proxy-reported scale of motor function in infants and young children with early-onset neuromuscular disorders (NMD), entitled the Proxy Motor Outcome Measure (PMOM).

Design: A mixed method design was employed, applying both qualitative and quantitative research.

Methods: A framework technique using sensitivity analyses guided the development of the most appropriate and relevant subset of items, modelled after 30 neuromuscular disease instruments/scales.

Assessing Motor Function in Congenital Muscular Dystrophy Patients Using Accelerometry.

Background: When tested in a controlled clinic environment, individuals with neuromuscular-related symptoms may complete motor tasks within normal predicted ranges. However, measuring activity at home may better reflect typical motor performance. The accuracy of accelerometry measurements in individuals with congenital muscular dystrophy (CMD) is unknown.

Understanding Symptoms in RYR1-Related Myopathies: A Mixed-Methods Analysis Based on Participants' Experience.

Background: In rare diseases such as ryanodine receptor 1-related myopathies (RYR1-RM), health-related quality of life (HRQoL) measures are critically important so clinicians and researchers can better understand what symptoms are most important to participants, with the ultimate goal of finding tangible solutions for them.

Objectives: The main objective of this study was to characterize symptoms in individuals with RYR1-RM to inform future research. A secondary objective of this study was to analyze positive and negative sentiments regarding symptoms and treatment effects post N-acetylcysteine (NAC) administration in individuals with RYR1-RM.

Correction to: Mixed methods analysis of Health-Related Quality of Life in ambulant individuals affected with RYR1-related myopathies pre-post-N-acetylcysteine therapy.

The article Mixed methods analysis of Health-Related Quality of Life in ambulant individuals affected with RYR1-related myopathies pre-post-N-acetylcysteine therapy, written by Carlos Capella-Peris, Mary M. Cosgrove, Irene C. Chrismer, Magalie Emile-Backer, M.

Intracellular calcium leak as a therapeutic target for RYR1-related myopathies.

RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1-related myopathies (RYR1-RM), a broad spectrum of rare neuromuscular disorders.

Mixed methods analysis of Health-Related Quality of Life in ambulant individuals affected with RYR1-related myopathies pre-post-N-acetylcysteine therapy.

Purpose: To characterize Health-Related Quality of Life (HRQoL) in ambulant individuals with RYR1-RM and to determine if a qualitative PRO tool (subjective self-assessment) complements PROMIS and Neuro-QoL scales to detect changes in HRQoL in ambulant individuals with RYR1-RM post N-acetylcysteine (NAC) treatment.

Methods: The study used a mixed methods research (MMR) design applying methodological triangulation. Qualitative data were collected via semi-structured interviews using open-ended questions.

Randomized controlled trial of -acetylcysteine therapy for -related myopathies.

Objective: To investigate the efficacy of -acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (-RM).

Methods: In this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance.

Motor function performance in individuals with RYR1-related myopathies.

Introduction: The objective of this study was to obtain a 6-month natural history of motor function performance in individuals with RYR1- related myopathy (RYR1-RM) by using the Motor Function Measure-32 (MFM-32) and graded functional tests (GFT) while facilitating preparation for interventional trials.

Methods: In total, 34 participants completed the MFM-32 and GFTs at baseline and 6-month visits.

Results: Motor deficits according to MFM-32 were primarily observed in the standing and transfers domain (D1; mean 71%).

Reliability and Validity of Self-Report Questionnaires as Indicators of Fatigue in RYR1-Related Disorders.

Background: RYR1-related disorders (RYR1-RD), are a spectrum of genetic neuromuscular disorders. Affected individuals frequently experience fatigue yet appropriate tools to assess RYR1-RD-associated fatigue remain underdeveloped.

Objective: This study assessed the reliability and validity of two self-report questionnaires, the multidimensional fatigue inventory (MFI-20) and adult/pediatric functional assessment of chronic illness-fatigue (FACIT-F/Peds-FACIT-F) as potential fatigue measures in RYR1-RD affected individuals.

Correlation of phenotype with genotype and protein structure in RYR1-related disorders.

Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population.

6-minute walk test as a measure of disease progression and fatigability in a cohort of individuals with RYR1-related myopathies.

Background: RYR1-related Myopathies (RYR1-RM) comprise a group of rare neuromuscular diseases (NMDs) occurring in approximately 1/90000 people in the US pediatric population. RYR1-RM result from pathogenic mutations in the ryanodine receptor isoform-1 (RYR1) gene where consequent RyR1 protein calcium dysregulation leads to impaired excitation-contraction coupling, oxidative and nitrosative stress, and mitochondrial depletion. These physiological deficits perpetuate RyR1 dysfunction causing further muscle injury, muscle weakness, and muscle fatigue.

Novel Variants in Individuals with -Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings.

The ryanodine receptor 1-related congenital myopathies (-RM) comprise a spectrum of slow, rare neuromuscular diseases. Affected individuals present with a mild-to-severe symptomatology ranging from proximal muscle weakness, hypotonia and joint contractures to scoliosis, ophthalmoplegia, and respiratory involvement. Although there is currently no FDA-approved treatment for RM, our group recently conducted the first clinical trial in this patient population (NCT02362425).