FormalPara Key Summary Points

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%).

Table 1 Demographics and clinical characteristics of participants with LGMD (N = 23)
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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.

Table 2 Symptoms and impacts of LGMD (N = 23)
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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%).

Table 3 Symptoms of LGMD that participants would like to improve first (N = 23)a
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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.

Fig. 1
figure 1

Conceptual model of LGMD symptoms and impacts

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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.