Materials and methods
Standard protocol approvals, registrations, and patient consents
Study design and procedures
Questions for all interviews
What are the symptoms of RYR1 related myopathy that give you the most trouble?
If there was one thing you would like a treatment to address, what would it be?
How much of the time is fatigue a problem?
Can you describe your fatigue?
What do you do to make the fatigue less of a problem?
What is your experience with others’ perspective of your symptoms?
How do you relate to others around your symptoms? Social, education, financial?
Is there anything else you would like to tell me about your quality of life?
How would you rate your quality of life?
Additional questions for post-intervention interviews
Did you observe that NAC or placebo alleviated any of the symptoms you mentioned that give you the most trouble? If so, could you elaborate on which symptoms?
How did the treatment affect fatigue specifically?
Research questions and hypothesis
29.8 ± 17.6
29.6 ± 17.1
28.3 ± 17.2
32.8 ± 16.3
23.8 ± 17.6
Adults (> 18)
39.9 ± 12.7
39.4 ± 12.4
41.3 ± 9.8
42.4 ± 7.3
39.7 ± 13.2
Peds (< 18)
10.2 ± 2.7
10.5 ± 2.8
10.5 ± 2.3
11.0 ± 2.9
10.1 ± 2.0
Quality of life > Social impacts: the most remarkable issue reported in interviews was a lack of other people’s understanding of RYR1 myopathies. Our first thought was to attribute this to the fact that RYR1-RM is rare and thus not understood by the general population. However, the interviewees’ comments focused primarily on their lack of apparent symptoms. As other people are not able to easily recognize a myopathy at first glance in milder cases, they tend to minimize the physical effects of the disease. This observation highlighted the conundrum of displaying visual symptoms. For this reason, participants struggled to explain their condition, typically choosing one of these options: giving very little information or saying nothing at all, using the name of a similar disease that is widely known such as Amyotrophic Lateral Sclerosis (ALS), or stating they have a “muscle condition” and describing its main symptoms (e.g., fatigue, pain, weakness, etc.). In addition, participants indicated similar situations happened on a daily basis, increasing the effect of this social issue. This subdomain revealed direct connections with several other domains such as symptoms, adaptive strategy, and future thoughts.
“when I'm standing up, generally I think it doesn’t, people don’t perceive that there’s a challenge that I have. When I have things like, I had it with the shuttle from the airport where I had to ask the gentleman to put down the wheelchair lift, and he kinda looked at me like ‘Well, you don’t look like anything’s wrong’, that sort of thing. Having to explain that I have a form of, I have muscular dystrophy, and I simply can’t do stairs or it’s too difficult for me to do, is generally how I explain it. Whether or not it’s believable… I think some folks don’t quite understand it. If something doesn’t look wrong, it can’t be wrong” < C04VA_MMC > Ref. 
Adaptive strategy > Physical behaviors: the most common solution mentioned for the main symptoms (e.g., fatigue, weakness, pain) was simply to cease activity and rest. This solution not only displayed a motor limitation, but also required increased organizational skills, as affected individuals needed more time to complete activities. Participants had to consider which activities were to take precedence, because they were not able to partake in all physical activities in which they would have liked to participate. Although these situations varied according to level of exertion, they reported a continuous and high degree of fatigue. This showed clear links between fatigue, psychological strategy, career/financial impact, and social impact subdomains.
“when I can't go anymore, I just stop, basically. And then I usually don't try to do any more that day, and just work on it another day a little bit… It will help some, but if I like, get to feeling a little better and then I start back, it will get worse. But it kind of depends on to what level of fatigue I get” (NAC) < C17VC_MMC > Ref. 
Adaptive strategy > Psychological strategy: whereas the previous paragraph explained how individuals with RYR1-RM faced effects of the disease from a functional approach, participants also used a psychological approach. The most common strategies included increased organization, learning from previous experiences, and applying problem solving to each situation. These strategies required a constant focus on how to improve their QoL, which actually reduced QoL. This created additional psychological fatigue that compounded the physical fatigue they experienced. There was also a tendency to compare themselves with healthy individuals, bringing attention to the problems they faced and feelings of frustration with limitations. This subdomain had connections with psychological factors, such as fears, anxiety, frustration, and self-esteem, as well as physical aspects, such as fatigue, weakness, pain, or physical behaviors.
“It makes any situation that much more complicated, ‘cause I have to take into account will I be able to do it? Will there be an obstacle? I think I plan ahead a lot more. I think like almost a military strategist in terms of what will happen in this event? Will there be stairs? Will I have to sit on the floor? If I have to do that, how will I handle that? It's a lot more of that. It's just draining in a way to constantly have to, as opposed I think people who don't aren't affected by things like this and can flow through life without having to worry about those things” < C36VA_ICC > Ref. 
Symptoms > Fatigue: participants reported their symptoms affected them on a daily basis, revealing the frequency of the disease’s impact. Indeed, most said these symptoms, not only fatigue but also weakness and pain, had a continuous influence in their lives, revealing the difficulties associated with their physical condition. For this reason, they limited and organized their daily activities, drastically reducing their ability to perform motor tasks. In addition, participants described their fatigue, using words such as “depletion”, “exhausted”, “empty”, “drained”, “having zero left in the tank”, which points to the benefit of potentially improving fatigue. As in previous cases, the concept of fatigue spread to other subdomains such as physical behavior, self-care/home maintenance, career/financial impact, and mobility.
“Probably daily. I don't really wake up feeling rested usually, and then I can usually do my daily morning stuff. I go to work. All that stuff, and then in the afternoon, typically, kind of when I'm winding down in the evenings. Sometimes, I'll need to take a nap before I do things around the house for kind of, like, round two at the house… It's just kind of like a general overall sleepiness. So, it's not like, I don't experience particular muscle fatigue in, like, a muscle group. It's just, if I do everything I need to do for the day, I'll come home, and I'll be tired so, I'll need to rest. It's not necessarily a muscular tired. It's more all over general fatigue” < C09VA_MMC > Ref. 
Future thoughts > Treatment desires: in general, participants expressed the symptoms they wanted most to be addressed by a potential treatment were fatigue and weakness. Having impairments in these areas limited physical performance considerably. Despite this, participants focused more on what they could do or what they could improve instead of dwelling on limitations. Similarly, they were committed to helping others rather than solely considering their own benefit. This revealed both a positive approach and a sense of social belonging related to the disease. All this information connected to several domains/subdomains in our research: quality of life, fatigue, social impact, positive aspects, and disease progression, strengthening the importance of the identified areas of analysis.
“I don't know if this would be the same thing or not, but I would say energy or zero fatigue… I am hopeful about this trial. And, while I don't know that it will provide a huge quality of life improvement for me, down the road if this and other trials help my children to have a much easier life, and I think that's why Brandon is participating… That I think those are all good things. And so, recently I went with my son to, he has a different neurologist than I do, and he was very hopeful about if not treatments, at least ways that we can manage muscular dystrophy going forward. It's not quite the hopeless condition that it once was” < C19VB_CCP > Ref. [1–2]
Post-intervention > Treatment benefits: several participants reported positive results of using NAC for treatment in RYR1-RM. The most valuable benefits were related to reducing fatigue and increasing strength. Additionally, several patients also experienced reduced pain, which could be indirectly produced by a reduction of tiredness and/or an increase of strength. These observations revealed some gain in their motor performance that in turn implied improvement in independence because they required less support in physical activities. Thus, some participants expressed access to a new and larger range of activities as well as a greater availability of time, suggesting that NAC impact was not limited to the physical domain. As expected, the strongest relationship for this subdomain was linked to the domain of symptoms, however, additional connections with other subdomains, such as physical behaviors, general assessment, or disease progression, were also present.
“It lessened it, I think. I don’t think I’m near as tired… I still can’t go up a flight of stairs without a handrail. But maybe it’s not quite as hard… I think there’s been little things that at the end of the day have equaled up to me not being as tired and as fatigued as I was because the completely washed out, complete drained, just can’t go no more” (NAC) < C32VC_CCP > Ref. 
“the weakness seems to be somewhat better. But it still exists, but it seems noticeably… I noticed it more in the first couple months, and then it seemed like it kind of hit a plateau and stayed at the same level throughout until the end… Like, yesterday, and since I’ve been on the medicine, I do notice that my recovery has been quicker than normal” (NAC) < C17VC_MMC > Ref. [1–3]
“They ruled my day from the moment I woke up in the morning. I woke up in pain every single morning. It was really significant. I wasn't aware of how severe my pain was even though I had – even knowing I was in pain, I couldn't really assess how severe it was until it was gone, because I had it my whole life. I was born with that level pain. I never had relief until six months ago. And it was breathtaking how dramatic it was not to have muscle pain, especially not to have ankle pain, to be able to wake up and then get up out of bed immediately instead of waking up and waiting up to two hours before I could get out of bed, because of the pain… And now I just, I go through the whole day. I don't even really have to think about it… But then to have to lie there staring at the ceiling and thinking about things and imagining what I would do and having to deal emotionally that frustration of wanting to get up and live and take care of my children and work” (NAC) < C38VC_CCP > Ref. 
Post-intervention > Side effects: participants reported very few side effects regarding RYR1-RM treatment with NAC. Side effects that were reported were minor (e.g., acid reflux or headaches). In one case, a participant reported potential increased fatigue, but later contradicted that report. This supported the minimal risk involved on this research. Due to the specificity of this subdomain there were no links to other areas of the study.
“I had extreme fatigue and I don't know if it's just because it was the weather change or if it was the drug or what, and then I've had a shift where I've had less fatigue… I do see some improvements. Like, I was able to go up the stairs yesterday for the PT trial without holding on the railing, which I have never been able to do” (NAC) < C01VC_CCP > Ref. 
“From the medicine I had? Headaches” (placebo) < C24VC_ICC > Ref. 
“Some acid reflux” (placebo) < C34VC_MMC > Ref. 
N in NAC group
N in Placebo group
Average changea in NAC group
Average changea in Placebo group
Difference between 2 groups
Lower limit of difference
Upper limit of difference
p valueb for zero difference
Neuro-QoL-participate in SRA