Abstract
Introduction
Limb girdle muscular dystrophies (LGMDs) are a group of rare and heterogeneous disorders involving progressive wasting of shoulder and pelvic girdle musculature. This study aimed to generate qualitative evidence on patient and caregiver experiences with symptoms and impacts of LGMD on overall function and daily life for sarcoglycanopathy subtypes 2C/R5, 2D/R3, and 2E/R4.
Methods
Twenty-three individuals with LGMD with (n = 5) or without (n = 18) a caregiver participated in 60-minute semi-structured video interviews. Interview transcripts were analyzed using thematic analysis. Differences in patient experience by ambulation status and LGMD subtype were examined.
Results
Participants were ambulatory (n = 14) and non-ambulatory (n = 9), representing three subtypes: 2C/R5 (n = 4), 2D/R3 (n = 12), and 2E/R4 (n = 7), with mean age of 34.8 years (SD = 16.08). 56.5% identified as female. Conceptual saturation was achieved within 18/23 interviews. Ambulatory participants identified difficulty with complex physical activities, e.g., running (n = 11, 78.6%), physical strength (n = 14, 100%), and difficulty with transfers, e.g., difficulty getting off the floor (n = 10, 71.4%). All non-ambulatory participants discussed problems with activities of daily living (ADLs) and transfers, e.g., getting in/out of bed and upper extremity function, particularly reaching (n = 8, 88.9%) and fine motor skills (n = 6, 66.7%). Fatigue and pain were reported by the majority of participants (n = 16, 69.6% and n = 19, 82.6%, respectively). A conceptual disease model was developed illustrating symptoms and impacts and their relationships to disease stage, capturing the patient experience across LGMD disease trajectory.
Conclusions
This study contributes to the limited evidence describing the patient experience of living with LGMD. The conceptual model can inform patient-centered assessment in future LGMD clinical trials.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Why carry out this study? |
Patients are uniquely positioned to provide insight into their experience of living with a disease and condition, including what changes in their condition would be meaningful for them. Little is known about how patients and their caregivers describe their experience living with limb girdle muscular dystrophies (LGMDs), including their expectations about treatment benefits. |
This study aimed to qualitatively explore patient and caregiver experience with symptoms of LGMD and their impact on overall function and daily life for sarcoglycanopathy subtypes 2C/R5, 2D/R3, and 2E/R4, and how changes in these symptoms and impacts would be meaningful or important to them. |
Sarcoglycanopathies as a group are associated with morbidity that has substantial impact on day-to-day functioning of affected patients. Left untreated, the disease progresses in severity, resulting in loss of ambulation and eventual death due to respiratory and/or cardiac impairment. There are currently no approved therapies to treat patients with sarcoglycanopathies. Therapeutic options are limited to physical therapy and investigational treatments. |
What was learned from the study? |
Ambulatory participants with LGMD identified difficulty with more complex physical activities (e.g., running, climbing stairs), physical strength (e.g., upper and lower extremity weakness), and difficulty with transfers (e.g., difficulty getting off the floor), while non-ambulatory participants discussed problems with activities of daily living (ADLs), transfers (e.g., getting in/out of bed), and upper extremity mobility. |
Longitudinal measures of physical strength, lower and upper extremity mobility, and fatigue are appropriate for inclusion in clinical trials of LGMD throughout disease progression. |
Introduction
Limb girdle muscular dystrophies (LGMDs) are a group of rare, genetically and phenotypically heterogeneous disorders involving progressive weakness and wasting of the shoulder and pelvic girdle musculature [1]. The estimated prevalence of LGMD is 0.8–6 per 100,000 [2,3,4,5,6,7,8]. LGMDs are caused by defects in multiple genes encoding for proteins residing within the sarcolemma, cytosol, or nucleus of the muscle cell [9]. LGMDs may be inherited in an autosomal dominant or recessive fashion, and more than 30 subtypes have been identified, with varying severity and age of symptom onset. Sarcoglycanopathy subtypes (known as 2D/R3, 2E/R4, 2C/R5, and 2F/R6) are a group of 4 primary autosomal recessive LGMDs caused by defects in the genes encoding 1 of the 4 cell membrane glycoproteins contributing to the sarcoglycan complex [10]. The sarcoglycan proteins (α-, β-, γ-, δ-, and, to a lesser extent, ε-SG) make up the sarcoglycan complex localized in the sarcolemma of muscle fibers. This complex acts as a link between the cytoskeleton and extracellular matrix, offering structural stability and protection from mechanical stress during muscle activity. This group of subtypes represents approximately 15% of all diagnosed LGMDs in the United States (US) [11], and 5–30% worldwide [2, 5, 12, 13]. Sarcoglycanopathy subtypes were recently reclassified and renamed, based on inheritance mode and order of discovery, into subtypes 2D/R3, 2E/R4, 2C/R5, and 2F/R6, although the original names are still used [2, 12, 14].
Sarcoglycanopathies are typically characterized by childhood to adolescent onset of disease, progressive weakness, and degeneration of skeletal muscle (i.e., proximal muscles of the pelvic and shoulder girdle), leading to loss of ambulation during adolescence in most patients [2, 11]. Other frequently reported clinical symptoms include exercise intolerance, hyperCKemia, calf and tongue hypertrophy, tiptoe gait pattern, tendon contracture, scapular winging, severe joint contracture, and scoliosis of the spine. Respiratory impairment affects all sarcoglycanopathy subtypes, and one study observed more severe symptoms in individuals with subtypes 2C/R5 and 2D/R3 [15]. Cardiac complications commonly affect subtypes 2C/R5 and 2E/R4 and rarely subtype 2D/R3 [2, 16, 17]. Patients with sarcoglycanopathies often have a more rapid and severe disease progression than other LGMD subtypes [2, 18], and are at high risk of early mortality due to respiratory and cardiac complications occurring in advanced stages of the disease.
As a group, sarcoglycanopathies are chronic and debilitating, with substantial impact on day-to-day functioning of affected patients, leading to significant lifetime morbidity. Today, there are no approved therapies that slow or stop the progression of any form of recessive LGMD. Consequently, there is an urgent medical need to develop a viable therapy for patients with LGMD, for whom supportive care is presently the only available option.
Living with a rare degenerative disease, such as LGMD, affects all aspects of life, including activities of daily living (ADLs), ability to work, and personal and family life [19]. The burden of LGMD is not only physical (i.e., progressive weakness in the hip and shoulder girdle muscles) but also emotional (i.e., distress, family burden), social (i.e., isolation, role limitation), and economic (i.e., medical and non-medical costs) [2]. Current treatments focus on management of symptoms and preventing and addressing complications [20]. To date, only a handful of peer-reviewed qualitative studies describe the symptoms and disease impacts that matter most to patients with LGMD and their caregivers, in which the sarcoglycanopathy subtypes 2D/R3, 2E/R4, and 2C/R5 were not well represented [21,22,23,24].
In one of the qualitative studies, interviews were conducted with 20 adults with LGMD to identify issues that had the greatest impact on their quality of life. The most commonly mentioned themes were mobility and ambulation, inability to carry out activities, social role limitations, emotional distress, and lower extremity weakness [24]. Aho et al. [21,22,23] employed a salutogenic perspective that focused on how daily life is comprehended, managed, and found to be meaningful among caregivers and patients with LGMD. Among patients, living with LGMD involves uncertainty about future health, physical and mental struggles to adjust continually to progressive deterioration, and dealing with a lack of knowledge of LGMD among professionals and society. Caregivers’ lives are impacted by their child’s disease via their evolving roles as caregivers as the disease progresses and a desire to have their child live a full, happy life.
The Patient-Focused Drug Development initiative by the US Food and Drug Administration (FDA) began in 2012 under the fifth authorization of the Prescription Drug User Fee Act [25]. Through patient engagement, this initiative has demonstrated that patients are the experts on what it is like to live with their condition, and that their chief complaints might not be factored explicitly into measures of treatment benefit in clinical trials. Recent FDA guidance underscores the importance of understanding patient perspectives on what is most important to them about how they experience a disease or condition, and how they hope to benefit from a successful treatment in order to identify clinical outcome assessments that are reliable and relevant to their disease experiences [26, 27].
Patient-reported health impacts of disease are uniquely important, as they provide valuable insights into a disease that could not be gained from biomedical outcomes alone. Therefore, this study sought to fill a gap in the literature by providing qualitative evidence about the patient experience of living with sarcoglycanopathy subtypes 2C/R5, 2D/R3, and 2E/R4, and their perceptions of overall health, disease course, and treatment expectations and goals. It also aimed to provide a conceptual model of LGMD signs and symptoms that can help guide the selection and measurement of outcomes important to patients with LGMD throughout disease progression [28]. Further, this study sought to highlight important symptoms and impacts that have the potential for improvement as a result of successful future therapy.
Methods
Study Design and Population
This cross-sectional, qualitative study was conducted in the US with individuals with LGMD 2C/R5, 2D/R3, and 2E/R4 with or without their caregiver. A semi-structured interview guide was used to guide the discussion and elicit symptoms and impacts of LGMD of importance to study participants. A US-based third-party recruitment agency recruited participants from their diverse profile of panel members; recruitment was supplemented with outreach through three patient advocacy groups, a sponsor-provided registry list, and a genetic counseling database. Study advertisements provided study contact details, and the recruitment agency screened all interested individuals. Eligible consenting and assenting individuals participated in one 60-minute semi-structured video interview between February 8 and May 4, 2021, and were remunerated US $125 in the form of an electronic gift card upon completion of their interview. The study protocol and all participant-facing materials were approved by a central Institutional Review Board (IRB), Advarra Center for IRB Intelligence, on January 15, 2021. The study was conducted in accordance with the Declaration of Helsinki, [29] the US FDA Good Clinical Practice Guidance, [27], and the International Society for Pharmacoeconomics and Outcomes Research PRO Good Research Practices Task Force recommendations for eliciting concepts [30]. Informed consent for participation and publication was obtained from study participants (or their parent or legal guardian for participants aged 4–17 years) before performing any study procedure. Assent was obtained from study participants aged 4–17 years.
Eligibility Criteria
Individuals were eligible to participate in the study if they had genetically confirmed LGMD 2C/R5, 2D/R3, or 2E/R4 and were age 4 years or older. Caregivers were eligible if they were the primary caregiver of an individual aged 4–17 years (inclusive) with genetically confirmed LGMD 2C/R5, 2D/R3, or 2E/R4. Eligible individuals could be “ambulatory,” defined in this study as using a wheelchair for part or none of the day, or “non-ambulatory,” defined as always using a wheelchair. Ambulatory status was assessed during the screening process and was confirmed during interviews.
Interview Procedures
Concept elicitation interviews were conducted by two postgraduate-level qualitative researchers (one master’s degree, one PhD). The semi-structured interview guide allowed respondents to first self-identify concepts of importance in their own voice, followed by prompts from the interviewer. To support the development of the interview guide, and to generate a list of potentially relevant prompts, recent publications regarding symptom prevalence in LGMD were reviewed [9, 21,22,23,24]. Open-ended questions were used to elicit the participant’s experience and perception of overall health and disease course; the frequency, severity, and degree of bother of reported symptoms; and the impacts of LGMD symptoms on overall functioning, daily activities, and well-being. Participants were also asked how they would define a successful or moderately successful treatment, including what symptoms they would like to see improve first. Adult participants (age 18 years and older) were interviewed individually. Interviews with children with LGMD, aged 4–17 years, were dyadic. For dyad interviews, questions were posed to the child, and the caregiver was asked for additional comments.
Data Analysis
Demographic and clinical characteristics of the study sample were quantitatively summarized. Continuous data are reported as means, standard deviations, and ranges, and categorical data are presented as percentages.
All interviews were audio-recorded and professionally transcribed for qualitative analysis. The qualitative interview data were analyzed using thematic analysis [31] and grounded theory [32] in NVivo™ [33]. Verbatim participant responses about their perceptions and experiences with LGMD were analyzed using a coding template, initially created to match the main topics in the interview guide. These phrases were grouped by key themes, attributes, concepts, and relationships.
The first six transcripts were double coded by two coders using the coding template. Coding discrepancies were reconciled by modification or re-definition of the coding template. After reconciliation, the remaining transcripts were coded by one coder. The coding template was updated throughout the coding process as new themes emerged. Revisions to the coding template were discussed by coders, and previously coded transcripts were recoded as needed.
After completion of coding, the research team evaluated the frequency of concepts raised, relationships between concepts, and the specific language used by participants. Symptoms and impacts reported were then analyzed and interpreted based on ambulation status. Concept saturation (i.e., the point at which no new concepts emerge) was examined using a saturation grid. Interviews were split into four groups: three groups of six interviews, and one group of five interviews. This allowed coders to track new concepts as they emerged, the number of participants mentioning each concept, and when no new concepts emerged [34].
Results
Study Population
Forty-five individuals with LGMD were identified for the study. Of those, 29 (64.4%) met eligibility criteria and 23 (51.1%) completed an interview. Of those who did not meet eligibility criteria (n = 16, 35.5%), the majority were excluded due to an unknown or ineligible subtype (n = 13, 28.9%). Participant characteristics are shown in Table 1. Participants were mostly ambulatory (n = 14, 60.9%), age 18 or older (n = 18, 78.3%), and diagnosed with LGMD subtype 2D/R3 (n = 12, 52.2%).
Key Themes of LGMD Patient Experience
During the interviews, participants identified a total of 40 symptoms and impacts (Table 2). Most symptoms and impacts (82.5%) reported appeared within the first group of 6 interviews. The remaining 17.5% appeared within the second and third interview groups of 6 interviews each (i.e., within the next 12 interviews). No new codes were identified in the final group of 5 interviews, demonstrating concept saturation.
Key themes included mobility and function of the lower extremities (e.g., standing, walking, going up and down stairs) and upper extremities (e.g., reaching, bending, fine motor skills), ADLs (e.g., bathing, getting dressed, toileting), and physical transfers (e.g., getting in and out of bed, getting up off the floor, sitting down). There were no observed differences in symptoms reported by LGMD subtype. When asked to describe their “worst” or most bothersome symptoms, participants frequently discussed upper and lower extremity weakness (i.e., issues with physical strength; n = 7, 30.4%) and pain (n = 10, 43.5%). The LGMD patient experience differed based on ambulation status and is described below.
Ambulatory Participants with LGMD
Among ambulatory participants (n = 14), the most commonly reported issues were associated with physical strength (n = 14, 100%), lower extremity mobility (n = 13, 92.9%), and ability to transfer (n = 12, 85.7%). In terms of ADLs, difficulty getting dressed was the most frequently reported challenge (n = 8, 57.1%). Pain (n = 11, 78.6%), mood disturbance (n = 10, 71.4%), and fatigue (n = 9, 64.3%) were also reported by ambulatory participants with LGMD.
Similarly, the most bothersome symptoms reported by ambulatory participants were issues with physical strength, including weakness in the lower extremities (n = 7, 50.0%) and the upper extremities (n = 4, 28.6%). One participant mentioned that “[…] what bothers me the most is I’m not able to do… physical activity continuously, … [due to] weakness here in the shoulders and legs.” Difficulties with lower extremity mobility and function (e.g., running n = 4, 28.6%) and pain (n = 7, 50.0%) were also bothersome. Another participant described their pain as “some muscle discomfort and pain or nerve pain” and that “it feels like maybe a cramping, but it’s not really a cramp, and it feels more weak.”
Non-Ambulatory Participants with LGMD
All non-ambulatory participants (n = 9, 100.0%) reported issues with upper and lower extremity mobility and function and the ability to transfer. The majority also reported challenges with physical strength (n = 8, 88.9%). Challenges with ADLs were reported by all non-ambulatory participants (n = 9, 100.0%), including bathing and feeding self/preparation of meals (both n = 7, 77.8%). Social impacts were also reported by all non-ambulatory participants with LGMD (n = 9, 100.0%), including one participant who stated “…I can’t get out. I’m stuck here unless somebody drives me somewhere.” Yet another described their experience as impacting their “ability to go over to people’s houses” and “make friends” because “people look at you different, people treat you different.”
Likewise, the most bothersome symptoms included issues with upper and lower extremity mobility and function (both n = 3, 33.3%). One participant noted that “the most bothersome is not being able to stand or walk.” Issues with physical strength, specifically upper extremity weakness (n = 3, 33.3%), and pain and mood disturbance (both n = 3, 33.3%) were also reported as bothersome by non-ambulatory participants. Other health problems (e.g., gastrointestinal function and respiratory issues) (n = 4, 44.4%) were also discussed, as reflected by the following quote: “[B]reathing, eating… [I]t’s more difficult to eat, like chewing [and] things like that. Then I’d say my stomach problems. [I get] constipation and bloating…”.
Treatment Expectations and Goals
During this interview study, participants were asked to describe treatment expectations and desirable treatment benefits. All participants (n = 23, 100.0%) reported that a treatment that maintained their current functioning would be beneficial, including one participant who stated, “it’s better than having a progressive wasting.” Further, the majority (n = 20, 87.0%) reported that a treatment that slowed the worsening of their symptoms would be beneficial. In the words of one participant, “if it slows it, anything’s better than a free fall.”
Participants commonly reported that an increase in physical strength would signal a successful (n = 10, 43.5%) or moderately successful (n = 5, 21.7%) treatment. Slowing the progression of the disease was also a sign of a successful (n = 7, 30.4%) or moderately successful (n = 8, 34.8%) treatment. Treatments that increase lower extremity mobility (n = 6, 26.1%) were also considered meaningful.
When asked which symptoms they would like to improve first when considering a new potential treatment for LGMD, a clear difference emerged by ambulation status (Table 3). Ambulatory participants desired improvement in physical strength (n = 7, 50.0%) and fatigue (n = 5, 35.7%), while non-ambulatory participants were hopeful for improved upper extremity mobility and function (n = 4, 44.4%) and other health conditions (n = 3, 33.3%).
Conceptual Model for Symptoms and Impacts of LGMD
Per FDA guidance, an initial conceptual framework can be hypothesized to support the measurement of the health-related quality of life concept(s) of interest in a given population (i.e., to determine what to measure) and should be supported by qualitative evidence [35]. For this study, a conceptual model was developed based on the concept elicitation interviews to provide a visual depiction of symptoms and impacts important to individuals with LGMD throughout disease progression (Fig. 1). The model includes ambulatory and non-ambulatory individuals with LGMD in order to display the salient symptoms as the disease progresses. Difficulty with physical strength is experienced throughout all phases of disease progression, whereas fatigue and difficulty with lower extremity mobility and function are important primarily in early stages of disease progression and loss of ambulation. The ability to transfer becomes important as ambulation wanes, and it continues to be important throughout the non-ambulatory phase. Upper extremity mobility and function become important in the non-ambulatory phase.
Discussion
In this qualitative interview study conducted with 23 individuals living with three different types of LGMD sarcoglycan deficiencies, we aimed to understand patient perceptions and experience of living with the disease, its impacts on their overall function and daily life, and treatment expectations. It extends the prior work of investigating the patient perspective of LGMD disease burden, which identified themes of limitations with mobility, difficulty performing activities, social role limitations, and emotional distress [24]. The most common symptoms and impacts reported by all participants in this study were related to lower extremity mobility and function, physical strength, difficulties with ability to transfer, and difficulties with ADLs. Pain, fatigue, and mood problems were also commonly reported.
These qualitative interviews highlighted the importance of ambulation status in patients’ and caregivers’ disease experience as well as their perceptions of potential treatment benefits. Further, differences in symptoms and impacts by ambulation status were clearly linked to the muscle groups most affected in the stage of disease progression (i.e., upper vs. lower extremities). No differences in symptoms and impacts were observed across the three sarcoglycan subtypes, with participants converging in terms of disease experience and desired potential treatment benefits.
Information from this study has been used to develop a conceptual disease model illustrating the patient experience across the LGMD disease trajectory, which can inform patient-centered clinical outcome assessment strategies for the evaluation of symptoms, disease impacts, and health-related quality of life in future studies of LGMD [27]. Difficulty with physical strength (i.e., muscle weakness) was consistently reported by participants throughout the disability trajectory; accordingly, measures of physical strength within a clinical trial setting with longitudinal administration would be appropriate across stages of disease progression. In contrast, difficulty with lower extremity mobility and function was more commonly reported in early stages of disease progression, prior to loss of ambulation. Consequently, inclusion of measures targeting lower extremity mobility would be relevant within a clinical trial of ambulatory participants, while assessment of upper extremity mobility (including ability to transfer) would be appropriate for participants beginning to experience loss of ambulation as well as fully non-ambulatory participants.
Although pain was mentioned as a bothersome symptom by half of the ambulatory participants and a third of non-ambulatory participants, pain reduction was infrequently reported as a treatment goal. Pain associated with limited mobility (including joint pain) was commonly reported, but does not seem to represent a major hurdle to participants, which may be due to its treatability with physical therapy, exercise, warm baths, and pain medication [36].
Fatigue is a common complaint among patients with muscular dystrophies [37], and was mentioned by more than half of ambulatory participants and a majority of non-ambulatory participants. As higher fatigue levels may be associated with lower quality of life among patients with LGMD [38], inclusion of longitudinal measures of fatigue in clinical trials should be considered.
Not surprisingly, non-ambulatory participants reported desired improvement in LGMD-associated health problems (e.g., gastrointestinal and respiratory issues) more frequently than ambulatory participants, as these distal health impacts tend to manifest with more advanced disease progression and the increased weakness and atrophy of legs, hips, abdomen, and shoulder muscle [39, 40].
These interviews further explored treatment expectations of patients and caregivers across three LGMD subtypes as well as which of the signs and symptoms they would prioritize if a treatment became available. All participants reported that an LGMD treatment that maintained their current functioning would be considered beneficial, likely because disease stabilization would represent a significant divergence from the natural history in which only a decline over time is possible [41]. Likewise, a treatment that slowed the worsening of their symptoms would be satisfactory and indicative of a successful treatment. Other earmarks of successful treatments included an increase in physical strength or lower extremity mobility.
Given the substantial heterogeneity in most rare diseases in terms of patient experience, an inherent challenge is identifying the most appropriate and salient patient-centered concepts of interest that have the potential for treatment benefit for a majority of patients [42]. By including a range of patients with varying characteristics (i.e., ambulation status, LGMD subtype, and age), we have been able to identify the core signs, symptoms, and impacts that may be relevant to most patients with LGMD, especially those with sarcoglycanopathy subtypes. The inclusion of caregivers alongside patients allowed representation of pediatric patients. The results highlight ambulation status as a characteristic defining and differentiating the patient experience as the disease progresses. For patients who maintain the ability to walk, they report issues with the lower extremity muscle groups associated with ambulation as these muscles are weight bearing. For those using a wheelchair, their priorities have shifted to issues in the upper extremity, as those muscle groups are of more use in their day-to-day life and are typically linked to self-perception of independence.
Some limitations were noted in this study. The interviews were conducted remotely via videoconference, and therefore, no formal testing of strength or mobility was performed. Patients may also have been unwilling to divulge all symptoms or impacts they experience to the interviewer due to social or emotional factors. Only sarcoglycanopathy subtypes of LGMD were included in this study, so the results may not be generalizable to all patients with LGMD. Also, not all LGMD subtypes were equally represented, with the majority being diagnosed with LGMD subtypes 2D/R3 and 2E/R4, the most common sarcoglycanopathies in the US [11]. The overall sample size of this study is relatively small, which is not uncommon in qualitative research in rare diseases, and is further consistent with that reported in the published literature [21,22,23]. The heterogeneous sociodemographic profile of the study sample, with regard to age, ethnicity, and educational status, contributes to the generalizability of these findings.
Conclusions
Although symptom prevalence in LGMD 2C/R5, 2D/R3, and 2E/R4 have been described before, either from anecdotal evidence or from healthcare providers treating experience, this study provides insights into what it is like to live with LGMD from the perspective of patients and their caregivers. In these interviews, we identified symptoms, impacts on daily life, and treatment goals of individuals with LGMD, which can be used to inform outcome measures in future clinical trials. Specifically, longitudinal assessment of physical strength, lower and upper extremity function, and fatigue would be useful for guiding patient-centered outcome measurement strategies for LGMD clinical trials. Additionally, of the LGMD subtypes, investigational therapies furthest along in development are for these three sarcoglycanopathies, providing further rationale for focusing the present study on these subtypes. Given the rare nature of these diseases, and generally similar clinical manifestations, findings from this qualitative study support the idea that one might be able to group three distinct sarcoglycan mutations together and validate a set of common outcome assessments. Although each sarcoglycanopathy subtype is small, we believe that the findings of this study will serve as the foundation for the exploration of other equally important LGMD subtypes in the future.
References
World Health Organization. World Health Organization. International Classification of Diseases version 11. 8C70.4 Limb girdle muscular dystrophy [Internet]. 2019. http://id.who.int/icd/entity/887807212
Georganopoulou DG, Moisiadis VG, Malik FA, Mohajer A, Dashevsky TM, Wuu ST, et al. A journey with LGMD: from protein abnormalities to patient impact. Protein J. 2021;40(4):466–88.
Theadom A, Rodrigues M, Roxburgh R, Balalla S, Higgins C, Bhattacharjee R, et al. Prevalence of muscular dystrophies: a systematic literature review. Neuroepidemiology. 2014;43:259–68.
Deenen JCW, Horlings CGC, Verschuuren JJGM, Verbeek ALM, Van Engelen BGM. The epidemiology of neuromuscular disorders: a comprehensive overview of the literature. Journal of Neuromuscular Diseases. 2015;2:73–85.
Liu W, Pajusalu S, Lake NJ, Zhou G, Ioannidis N, Mittal P, et al. Estimating prevalence for limb-girdle muscular dystrophy based on public sequencing databases. Genet Med. 2019;21(11):2512–20.
Magri F, Nigro V, Angelini C, Mongini T, Mora M, Moroni I, et al. The italian limb girdle muscular dystrophy registry: relative frequency, clinical features, and differential diagnosis. Muscle Nerve. 2017;55(1):55–68.
Winckler PB, da Silva AMS, Coimbra-Neto AR, Carvalho E, Cavalcanti EBU, Sobreira CFR, et al. Clinicogenetic lessons from 370 patients with autosomal recessive limb-girdle muscular dystrophy. Clin Genet. 2019;96(4):314–53.
Pagola-Lorz I, Vicente E, Ibáñez B, Torné L, Elizalde-Beiras I, Garcia-Solaesa V, et al. Epidemiological study and genetic characterization of inherited muscle diseases in a northern Spanish region. Orphanet J Rare Dis. 2019;14(1):276.
Murphy AP, Straub V. The classification, natural history and treatment of the limb girdle muscular dystrophies. J Neuromuscul Dis. 2015;22:S7-19.
Sandonà D, Betto R. Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects. Expert Rev Mol Med. 2009;11: e28.
Moore SA, Shilling CJ, Westra S, Wall C, Wicklund MP, Stolle C, et al. Limb-girdle muscular dystrophy in the United States. J Neuropathol Exp Neurol. 2006;65:995–1003.
Wicklund MP. The limb-girdle muscular dystrophies. Contin Lifelong Learn Neurol. 2019;25(6):1599–618.
Mahmood OA, Jiang XM. Limb-girdle muscular dystrophies: Where next after six decades from the first proposal (Review). Mol Med Rep. 2014;9:1515–32.
Straub V, Murphy A, Udd B. 229th ENMC international workshop: Limb girdle muscular dystrophies—nomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017. Neuromuscul Disord. 2018;28:702–10.
Politano L, Nigro V, Passamano L, Petretta V, Comi LI, Papparella S, et al. Evaluation of cardiac and respiratory involvement in sarcoglycanopathies. Neuromuscul Disord. 2001;11(2):178–85.
Semplicini C, Vissing J, Dahlqvist JR, Stojkovic T, Bello L, Witting N, et al. Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E. Neurology. 2015;84(17):1772–81.
Narayanaswami P, Weiss M, Selcen D, David W, Raynor E, Carter G, et al. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neur. Neurology. 2014;83(16):1453–63.
Alonso-Pérez J, González-Quereda L, Bello L, Guglieri M, Straub V, Gallano P, et al. New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy. Brain. 2020;143(9):2696–708.
FDA. Limb Girdle Muscular Dystrophies (LGMD) FDA Patient-led Listening Session [Internet]. 2020 [cited 2022 Jan 7]. https://img1.wsimg.com/blobby/go/cd065915-4798-409e-aec1-fc8fb5c2266c/LimbGirdleMuscularDystrophySummary-0002.pdf
Chu ML, Moran E. The limb–girdle muscular dystrophies: is treatment on the horizon? Neurotherapeutics. 2018;15:849–62.
Aho AC, Hultsjö S, Hjelm K. Young adults experiences of living with recessive limb-girdle muscular dystrophy from a salutogenic orientation: an interview study. Disabil Rehabil. 2015;37(22):2083–91.
Aho AC, Hultsjö S, Hjelm K. Experiences of being parents of young adults living with recessive limb-girdle muscular dystrophy from a salutogenic perspective. Neuromuscul Disord. 2017;27(6):585–95.
Aho AC, Hultsjo S, Hjelm K. Perceptions of the transition from receiving the diagnosis recessive limb-girdle muscular dystrophy to becoming in need of human support and using a wheelchair: an interview study. Disabil Rehabil. 2019;41(19):2289–98.
Hunter M, Heatwole C, Wicklund M, Weihl CC, Mozaffar T, Statland JM, et al. Limb-girdle muscular dystrophy: a perspective from adult patients on what matters most. Muscle Nerve. 2019;60:419–24.
FDA. PDUFA V: Fiscal Years 2013 - 2017 [Internet]. 2012 [cited 2022 Jun 13]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863890/
FDA. Patient-Focused Drug Development: Methods to Identify What Is Important to Patients. Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders [Internet]. 2022 [cited 2022 Mar 8]. https://www.fda.gov/media/131230/download
FDA. Discussion Document for Patient-Focused Drug Development Public Workshop on Guidance 3: Select, Develop or Modify Fit-For-Purpose Clinical Outcome Assessments [Internet]. 2018 [cited 2022 Jan 5]. https://www.fda.gov/media/116277/download
Rothman ML, Beltran P, Cappelleri JC, Lipscomb J, Teschendorf B, Sloan JA. Patient-reported outcomes: conceptual issues. Value Heal. 2007;10(Suppl 2):S66-75.
World Medical Association. Declaration of Helsinki. Ethical principles for medical research involving human subjects [Internet]. 2018 [cited 2020 Jul 3]. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
Patrick DL, Burke LB, Gwaltney CJ, Leidy NK, Martin ML, Molsen E, et al. Content validity—establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO good research practices task force report: Part 1—eliciting concepts for a new PRO instru. Value Heal. 2011;14(8):967–77.
Braun V, Clarke V, Hayfield N, Terry G. Thematic analysis. In: Handbook of Research Methods in Health Social Sciences. 2019. p. 843–60.
Bryant A, Charmaz K. The SAGE Handbook of Grounded Theory. The SAGE Handbook of Grounded Theory. 2012.
NVivo (Version 12). QSR International Pty Ltd [Internet]. 2018 [cited 2023 Feb 1]. https://www.qsrinternational.com/nvivo-qualitative-data-analysis-software/home
Rothman M, Burke L, Erickson P, Leidy NK, Patrick DL, Petrie CD. Use of existing patient-reported outcome (PRO) instruments and their modification: The ISPOR good research practices for evaluating and documenting content validity for the use of existing instruments and their modification PRO task force report. Value Heal. 2009;12(8):1075–83.
US Food and Drug Administration. Guidance for Industry Patient-Reported Outcome Measures Use in Medical Product Development to Support Labeling Claims. Clinical/Medical Federal Register. 2009.
MDA (Muscular Dystrophy Association). Limb-Girdle Muscular Dystrophy (LGMD) [Internet]. [cited 2022 Mar 9]. https://www.mda.org/disease/limb-girdle-muscular-dystrophy/signs-and-symptoms
Angelini C, Tasca E. Fatigue in muscular dystrophies. Neuromuscul Disord. 2012;22(3–3):S214–20.
Peric M, Peric S, Stevanovic J, Milovanovic S, Basta I, Nikolic A, et al. Quality of life in adult patients with limb–girdle muscular dystrophies. Acta Neurol Belg. 2018;118(2):243–50.
Bushby K. Limb-Girdle Muscular Dystrophies [Internet]. National Organization for Rare Disorders (NORD) Rare Disease Database. 2012 [cited 2022 Mar 9]. https://rarediseases.org/rare-diseases/limb-girdle-muscular-dystrophies
Fayssoil A, Ogna A, Chaffaut C, Chevret S, Guimarães-Costa R, Leturcq F, et al. Natural history of cardiac and respiratory involvement, prognosis and predictive factors for long-term survival in adult patients with limb girdle muscular dystrophies type 2C and 2D. PLoS ONE. 2016;11(4): e0153095.
Pozsgai E, Griffin D, Potter R, Sahenk Z, Lehman K, Rodino-Klapac LR, et al. Unmet needs and evolving treatment for limb girdle muscular dystrophies. Neurodegener Dis Manag. 2021;11(5):411–29.
Benjamin K, Vernon MK, Patrick DL, Perfetto E, Nestler-Parr S, Burke L. Patient-reported outcome and observer-reported outcome assessment in rare disease clinical trials: An ISPOR COA emerging good practices task force report. Value Heal. 2017;20(7):838–55.
Acknowledgements
Thanking Patient Participants
The authors would like to thank the interview participants for taking time to share their perspectives and the Speak Foundation, Kurt + Peter Foundation, and LGMD2D Foundation for their support with outreach.
Funding
This work was sponsored by Sarepta Therapeutics, Inc. Sarepta Therapeutics, Inc. is also funding the journal's Rapid Service and Open Access Fees.
Authorship
All authors made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data. All authors drafted or critically revised this submission, approved the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy of integrity of any part of the work are appropriately investigated and resolved.
Authors’ Contributions
Study design: Cristina Casstevens, Vanessa Perez Patel, Elizabeth Merikle, Ivana Audhya. Data extraction: Kelly Johnston, Cristina Casstevens, Vanessa Perez Patel, Elizabeth Merikle. Analyses: Kelly Johnston, Cristina Casstevens, Vanessa Perez Patel, Elizabeth Merikle. Interpretation of data: Kelly Johnston, Cristina Casstevens, Vanessa Perez Patel, Elizabeth Merikle, Carrie Presnall, Ivana Audhya. Writing first manuscript draft: Kelly Johnston, Elizabeth Merikle, Carrie Presnall. Manuscript revision: Kelly Johnston, Elizabeth Merikle, Carrie Presnall. All authors have read and approved the final manuscript.
Prior Presentation
A summary of this manuscript was presented during a virtual poster presentation with ISPOR in May 2022.
Disclosures
Ivana Audhya is an employee of Sarepta Therapeutics, Inc. Kelly Johnston, Elizabeth Merikle, and Carrie Presnall are employees of Labcorp Drug Development, and Cristina Casstevens and Vanessa Perez Patel were previously employed by Labcorp Drug Development, which received funds from Sarepta Therapeutics, Inc to conduct this study. Cristina Casstevens is affiliated with the Neurobehavioral Institute of Austin (Austin, TX). Vanessa Perez Patel is affiliated with Organon (Jersey City, NJ).
Compliance with Ethics Guidelines
The study protocol and all participant-facing materials were approved by Advarra Center for IRB Intelligence (a central IRB) on January 15, 2021. The study was conducted in accordance with the Declaration of Helsinki, [29] US FDA Good Clinical Practice Guidance, [27] and the International Society for Pharmacoeconomics and Outcomes Research PRO Good Research Practices Task Force recommendations for eliciting concepts [30]. Informed consent for participation and publication was obtained from study participants (or their parent or legal guardian for participants aged 4–17) before performing any study procedure. Assent was obtained from study participants aged 4 to 17 years.
Data Availability
The data generated and analyzed during this study are available from the corresponding author upon reasonable request.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
About this article
Cite this article
Johnston, K., Casstevens, C., Patel, V.P. et al. Concept Elicitation Interviews and Conceptual Model to Understand the Patient Experience of Limb Girdle Muscular Dystrophy. Adv Ther 40, 2296–2310 (2023). https://doi.org/10.1007/s12325-023-02463-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12325-023-02463-8