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. Quantitative data were gathered through PROMIS and Neuro-QoL instruments. Additionally, qualitative data were transformed into quantitative data for subjective self-assessment and frequency analyses. Results: Qualitative results identified five domains and 33 subdomains as areas of interest. The most valuable were the importance of social impacts, the development of several coping strategies, both physical and psychological, and the identification of fatigue and weakness as key symptoms. Data transformation then categorized more than 3100 citations on frequency analyses, globally and by domain, visit, and participant. Regarding quantitative results, there was no clear evidence that any of the three PRO tools captured positive changes as a result of NAC treatment. Conclusion: Qualitative results showed a comprehensive characterization of HRQoL in this population based on a symptom/patient-centered approach. These findings will inform future studies. Furthermore, given the similar findings across our multiple methods and endpoints, the introduction of MMR may be a valuable, complementary approach to clinical trials. MMR may be especially useful to incorporate in order to address and follow the FDA's guidance and prioritization on the inclusion of affected individuals' perspectives in clinical trials

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. Methods: The study used a mixed-methods design applying methodological triangulation. Qualitative data were collected via semi-structured interviews at three visits to characterize symptoms in individuals with RYR1-RM and to analyze treatment effects. Qualitative data were then transformed into quantitative results to measure the frequency with which each symptom was mentioned by participants. Results: A total of 12 symptoms were identified as areas of interest to participants with RYR1-RM, highlighting fatigue and weakness as key symptoms. Data transformation categorized more than 1000 citations, reporting a greater number of positive comments for post-intervention interviews than for baseline and pre-intervention visits and that NAC group participants stated more positive comments regarding treatment effect than did the placebo group. Conclusions: We present a comprehensive characterization of symptoms in RYR1-RM and how those symptoms influence HRQoL. Furthermore, the introduction of mixed methods may be a valuable way to better understand patient-centered data in rare diseases to support affected individuals in coping with their symptoms

Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy and Related Neurological Disorders

The recent advances in nucleic acid therapeutics demonstrate the potential to treat hereditary neurological disorders by targeting their causative genes. Spinal and bulbar muscular atrophy (SBMA) is an X-linked and adult-onset neurodegenerative disorder caused by the expansion of trinucleotide cytosine-adenine-guanine repeats, which encodes a polyglutamine tract in the androgen receptor gene. SBMA belongs to the family of polyglutamine diseases, in which the use of nucleic acids for silencing a disease-causing gene, such as antisense oligonucleotides and small interfering RNAs, has been intensively studied in animal models and clinical trials. A unique feature of SBMA is that both motor neuron and skeletal muscle pathology contribute to disease manifestations, including progressive muscle weakness and atrophy. As both motor neurons and skeletal muscles can be therapeutic targets in SBMA, nucleic acid-based approaches for other motor neuron diseases and myopathies may further lead to the development of a treatment for SBMA. Here, we review studies of nucleic acid-based therapeutic approaches in SBMA and related neurological disorders and discuss current limitations and perspectives to apply these approaches to patients with SBMA

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

Abstract 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. Muscle weakness and fatigue are two primary complaints in patients with RYR1-RM and are major symptoms that limit the ability of individuals to perform activities of daily living. The six-minute walk test (6MWT) is an endurance test with high reliability and validity used to measure walking capacity, disease progression, and more recently, fatigability in NMDs with limited results in RYR1-RM. Therefore, the purpose of our study is to objectively assess disease progression and fatigability in RYR1-RM affected individuals using the 6MWT. We hypothesized that 6MWT distance and fatigability would not change significantly between 0 and 6-month visits in RYR1-RM patients, given the clinically reported stable or slowly progressive nature of the disease. We also hypothesized participants would show fatigability during the 6MWT, given muscle weakness and fatigue are the two primary complaints of affected individuals. Results As expected, paired t-test analyses revealed no significant difference between total distance traveled (p = .608) or percent change in speed (p = .141) at 0-months compared with the 6-month visit. Fatigability was observed given the decline in speed between the first and last minute of the 6MWT at the 6-month time point (p ≤ .0005,). Although this decline was not significant at baseline, a significant decline in speed from the 1st minute did occur at minutes 2, 3, and 4 during the baseline visit. Conclusion In this RYR1-RM cohort, the 6MWT showed disease stability over a 6-month period but revealed fatigability during the test. Given these results, the 6MWT may be a promising endpoint for evaluating fatigability and therapeutic efficacy in the 6-month treatment phase of our current n-acetylcysteine trial in this population. Improvement post intervention could be attributed to the intervention rather than variability in disease progression. Trial Registration Clinical Trials.gov, NCT02362425, Registered 13 February 2015-Prospectively registered

Transferability and Fine Mapping of genome-wide associated loci for lipids in African Americans

BACKGROUND: A recent, large genome-wide association study (GWAS) of European ancestry individuals has identified multiple genetic variants influencing serum lipids. Studies of the transferability of these associations to African Americans remain few, an important limitation given interethnic differences in serum lipids and the disproportionate burden of lipid-associated metabolic diseases among African Americans. METHODS: We attempted to evaluate the transferability of 95 lipid-associated loci recently identified in European ancestry individuals to 887 non-diabetic, unrelated African Americans from a population-based sample in the Washington, DC area. Additionally, we took advantage of the generally reduced linkage disequilibrium among African ancestry populations in comparison to European ancestry populations to fine-map replicated GWAS signals. RESULTS: We successfully replicated reported associations for 10 loci (CILP2/SF4, STARD3, LPL, CYP7A1, DOCK7/ANGPTL3, APOE, SORT1, IRS1, CETP, and UBASH3B). Through trans-ethnic fine-mapping, we were able to reduce associated regions around 75% of the loci that replicated. CONCLUSIONS: Between this study and previous work in African Americans, 40 of the 95 loci reported in a large GWAS of European ancestry individuals also influence lipid levels in African Americans. While there is now evidence that the lipid-influencing role of a number of genetic variants is observed in both European and African ancestry populations, the still considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of these traits

Transferability and Fine Mapping of genome-wide associated loci for lipids in African Americans

Abstract Background A recent, large genome-wide association study (GWAS) of European ancestry individuals has identified multiple genetic variants influencing serum lipids. Studies of the transferability of these associations to African Americans remain few, an important limitation given interethnic differences in serum lipids and the disproportionate burden of lipid-associated metabolic diseases among African Americans. Methods We attempted to evaluate the transferability of 95 lipid-associated loci recently identified in European ancestry individuals to 887 non-diabetic, unrelated African Americans from a population-based sample in the Washington, DC area. Additionally, we took advantage of the generally reduced linkage disequilibrium among African ancestry populations in comparison to European ancestry populations to fine-map replicated GWAS signals. Results We successfully replicated reported associations for 10 loci (CILP2/SF4, STARD3, LPL, CYP7A1, DOCK7/ANGPTL3, APOE, SORT1, IRS1, CETP, and UBASH3B). Through trans-ethnic fine-mapping, we were able to reduce associated regions around 75% of the loci that replicated. Conclusions Between this study and previous work in African Americans, 40 of the 95 loci reported in a large GWAS of European ancestry individuals also influence lipid levels in African Americans. While there is now evidence that the lipid-influencing role of a number of genetic variants is observed in both European and African ancestry populations, the still considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of these traits.</p

Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings

The ryanodine receptor 1-related congenital myopathies (RYR1-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 RYR1-RM, our group recently conducted the first clinical trial in this patient population (NCT02362425). This study aimed to characterize novel RYR1 variants with regard to genetic, laboratory, muscle magnetic resonance imaging (MRI), and clinical findings. Genetic and histopathology reports were obtained from participant’s medical records. Alamut Visual Software was used to determine if participant’s variants had been previously reported and to assess predicted pathogenicity. Physical exams, pulmonary function tests, T1-weighted muscle MRI scans, and blood measures were completed during the abovementioned clinical trial. Six novel variants (two de novo, three dominant, and one recessive) were identified in individuals with RYR1-RM. Consistent with established RYR1-RM histopathology, cores were observed in all biopsies, except Case 6 who exhibited fiber-type disproportion. Muscle atrophy and impaired mobility with Trendelenburg gait were the most common clinical symptoms and were identified in all cases. Muscle MRI revealed substantial inter-individual variation in fatty infiltration corroborating the heterogeneity of the disease. Two individuals with dominant RYR1 variants exhibited respiratory insufficiency: a clinical symptom more commonly associated with recessive RYR1-RM cases. This study demonstrates that a genetics-led approach is suitable for the diagnosis of suspected RYR1-RM which can be corroborated through histopathology, muscle MRI and clinical examination