NIH Research Festival
Introduction: Mutations in RYR1 disrupt RyR1 protein function, resulting in RYR1-related myopathies (RYR1-RM). Symptoms include muscle weakness, motor delay, fatigue, myalgia, scoliosis and, in severe cases, ophthalmoplegia and/or respiratory insufficiency. Genotype-phenotype profiles were evaluated to determine whether mutation location affects symptom severity based on clinical presentation and motor function as determined by the Motor Function Measure (MFM32) assessment. Methods: 40 participants were sorted into 2 of the 3 protein domains (n-terminus, central/transmembrane, or both) based on RyR1 mutations. Clinical symptoms and MFM32 dimension performance percentages were assigned to each participant. ANOVA was used to compare the mean number of total symptoms for each group of mutations. MFM32 dimension (D1, D2, and D3) percentages were compared between protein domains using Kruskal-Wallis (adjusted p-value for repeated analysis at 0.012). Results: Although there was no difference in the number of symptoms per domain, 92% of N-terminus mutations resulted in proximal/truncal muscle weakness. The most common symptoms for both N- and C-terminus mutations were proximal/truncal weakness, muscle rigidity/contractures, and facial weakness/ptosis. Motor function performance was also similar between domains as there was no difference in MFM32 dimension performances. Yet, the greatest deficit in motor function was related to tasks performed from a standing position as determined by the mean D1%. Conclusion: We identified two symptoms that presented in patients with mutations in the N-terminus domain and 3 symptoms that presented in patients with mutations in the Central domain only. However, no patients had mutations in the C-terminus of the protein, and we did not find any significant difference in number of symptoms or motor function between protein domain groups. Additional work is ongoing to further elucidate these findings.
Scientific Focus Area: Genetics and Genomics
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