Self-regulation in Barth syndrome: a qualitative perspective of adolescents, adults and parents in the U.K

Background Barth syndrome (BS) is a life-threatening genetic disease caused by abnormal lipids in the mitochondria of cells and mostly affects young males. Those living with BS have severe exercise intolerance, lethargy and fatigue due to muscle disease which affect their daily life. Previous research suggests a need for qualitative exploration of self-regulation in BS and the inter-personal processes at play in family life. Therefore this study aimed to explore self-regulation and coping strategies and inter-personal responses in individuals and families affected by Barth syndrome. A multi-perspective qualitative study based on face to face, semi-structured, in-depth interviews with 11 participants (9–27 years, mean 15 years) with BS and/or their parents participating in a randomised double-blind clinical drug trial (CARDIOMAN). Interviews were transcribed verbatim and managed in NVivo prior to conducting a thematic analysis (AS and GH). Results Four key themes were identified: diagnosis and treatment, social support, identity and social integration, symptoms and self-regulation. The present findings suggest that self-regulation and coping in boys with BS was interpersonal and contingent on parental awareness such that parents were aware that their child had a limited energy reserve and that had to be managed due to the implications of fatigue for daily living. Conclusion The findings support previous quantitative work demonstrating that children and parents tend to share a coherent view of BS. However, there is a need for greater awareness from others within the wider context of social and employment networks to minimise adverse implications for future life choices.


Introduction
Barth syndrome is a life-threatening genetic disease caused by abnormal lipids in the mitochondria of cells, mostly affecting young males. At present, there are twenty-seven patients with the disease treated in the U.K. Barth Syndrome Service. The presentation of Barth syndrome (MIM 302060) typically includes skeletal muscle weakness, neutropenia, and growth retardation [1,2]. In addition, two metabolic abnormalities are typically present; elevated urinary excretion of 3-methylglutaconic acid and hypocholesterolemia [2]. Furthermore, a mild cognitive phenotype has been described [3] and there is individual variability in the age of onset, the expression of symptoms, and progression of the disease.
Those affected can develop heart failure during the first decade of life and can struggle with poor growth or feeding problems during childhood. Serious bacterial infection is another life-threatening issue due to low blood neutrophil counts in 90% of patients [4]. As a result, two thirds of UK patients require chronic subcutaneous injection therapy with granulocyte colony stimulating factor (G-CSF), a distressing and expensive medication provided by the UK National Health Service (NHS). They often remain intermittently neutropenic despite receiving G-CSF.
There can be rapid deterioration during periods of stable health and even when under expert medical care. Ventricular arrhythmia (tachycardia or fibrillation) affects 10% of adolescents and can cause sudden cardiac death at any stage of childhood, including the neonatal period [5]. These seemingly random acute crises are not predictable by genotype or recent medical history, producing a need for cardiac resuscitation training, use of automated external defibrillators and/or implanted cardiac reveal devices, and causing chronic anxiety in affected families. Twenty-two percent of boys living in the UK have undergone cardiac transplantation and others require ongoing management for cardiomyopathy, yet patients continue to die from this disease despite best conventional therapy.

Psychosocial impact in Barth Syndrome
Those living with BS experience severe exercise intolerance, lethargy and fatigue which affects their daily life. Lethargy and fatigue can interfere with schoolwork and play and often necessitates the use of wheelchairs. Similarly, patients are compromised in their ability to hold down strenuous or demanding jobs which impacts quality of life and ability to obtain employment [6].
Patients and their families often experience many daily challenges associated with the disease, as well as major healthcare costs associated with transplantation, medications and limitations around employment.
The management of neutropenia in this disease is challenging since patients have highly variable neutrophil counts, preventing administration of a consistent daily dose and requiring repeated blood counts and clinical management. Recurrent subcutaneous injections and repetitive blood counts can produce needle phobia and compliance issues.
Previous quantitative approaches to measuring quality of life and the psychosocial impact of living with BS have been conducted in the US. For example, Storch et al. [7] found that self-reported quality of life was lower in young people with BS compared with healthy peers; they were also more socially isolated and displayed less independent functioning than healthy peers. In addition, their parents saw a need for academic assistance for their child. A pertinent aspect of this study is that young people with Barth Syndrome rated their own psychosocial functioning in a way that was consistent with their parents' rating. Such parent-child coherence is not typically seen in families of children with chronic illness, where parents typically report more observed problems than those reported by their child [8].
A further study showed that individuals with BS exhibited poorer quality of life, physical functioning and social functioning than individuals with diabetes and cancer, based on both parental and child reports [9]. This study also measured the psychological functioning in parents of individuals with BS with parents reporting higher 'internalised' care-giver strain, such as negative feelings, compared to objective or 'externalised' strain such as disruptions to daily life like schedule changes. Furthermore, parents were adaptive rather than maladaptive in their response to their child's illness and demonstrated acceptance, positive reframing, emotional support and instrumental support. These observations are a realistic reflection of caregiver anxieties regarding a child's prognosis and long-term health concerns.

Self-regulation and coping
Self-regulation is defined as the ability to modulate cognition, emotion and behaviour toward a goal and includes both individual and interpersonal goals [10]. Self-regulation in chronic illness includes interpersonal processes such as the ability to use interpersonal resources in their environment [11]. Past research suggests that adolescents must also regulate their cognitive, emotional, and behavioural responses to unrequested parental involvement in disease management, such as parental monitoring, disclosure and family conflict [12]. Typically, the interpersonal context in paediatric research is characterised in the way that parents, peers, and health professionals influence disease management. Evidence for the importance of adolescents' self-regulation skills in these interpersonal processes comes from studies showing that parental involvement and knowledge are actually reflective of how adolescents involve their parents in chronic illness management [13].

Self-regulation and coping strategies in Barth syndrome
Coping strategies are also defined as the cognitive, emotional and behavioural means by which individuals manage the symptoms and daily living with a condition [14]. To date there is little research that has qualitatively explored the lived experience and coping strategies in BS. However, (Mazar et al. [15] explored the experience of living with BS from the perspective of older adult males (above 35 years of age). This study mostly focused on signs and symptoms of BS but also evaluated coping strategies. Individuals' coping strategies included adapting daily routines, managing physical limitations and emotional responses. Signs and symptoms were found to impact negatively on individuals' emotional, physical, social and role functioning from an early age into adulthood.
The present qualitative research is based within the context of a clinical trial in which the participant and family experience of BS and their participation in the trial were also documented. This embedded qualitative research enabled the authors to explore self-regulation and coping and the inter-personal responses in individuals and families affected by Barth syndrome.

Ethical approval
Ethical approval for the qualitative interview study was granted as part of the clinical trial within which it was conducted (REC ref: 15/SW/0228) on 12/11/2015.

Participants
The participants were in a double blind, crossover, randomised controlled trial of the oral drug bezafibrate (CARDIOMAN trial; see "Appendix 1" for selection criteria) and consisted of 7 males aged 14 years and above and 4 males below 14 years. Participants aged 14 and above were interviewed, along with the attending parents of all participants. The interview data formed the basis of evaluating trial participation as well as gaining insight into living with the disease. All patients are under the care of the national NHS Specialised Services Barth Syndrome Service, which is based at Bristol Royal Hospital for Children. Participants and their families attend this service from across the UK.

Topic guides
Topic guides were developed for interviews conducted at both phases of the crossover trial (4 and 9 months) based on discussions with the study team and grant co-applicants, which include medical specialists.
The topic guide for phase 1 included items in relation to: family, schooling, occupation, diagnosis of BS, symptoms of BS, previous and current treatment for BS, living with BS and physical impact, quality of life, social and psychological impact of BS, support, adherence and/ or issues with medication and engagement with medical practitioners.
The topic guide for phase 2 of the trial was limited to: symptoms of BS, experience of the trial, quality of life, social and psychological impact of BS, adherence and/ or issues with medication and engagement with medical practitioners.

Interviews
Face-to-face semi-structured interviews were conducted with seven participants in the CARDIOMAN trial aged 14 and above, and four interviews with parents of those aged under 14 years (see Table 1 for details of interview context). All interviews were conducted in a private room whilst families were attending a clinical assessment unit for the study. Written informed consent for all interviews was obtained prior to the first phase of interviews. Parents of children gave their consent for their own and their child's participation but children under 14 were not interviewed (although were in the room as their parent/s were interviewed). Participants aged 14 years and above were interviewed alone or with a parent if preferred, and two adult participants were interviewed alone. A total of 22 interviews were conducted at two time-points: following the first treatment phase (at 4 months) and at the end of phase 2 (at 9 months).

Analysis
All the interviews were audio-recorded and transcribed verbatim. A sample of six transcripts representing both time-points were read and re-read by two experienced qualitative researchers (AS and GH) to familiarise themselves with the data. AS and GH then met to discuss their overall impressions of the whole dataset and an inductive thematic analysis was conducted on both data sets [16]. Both AS and GH independently coded the transcripts and then met again to discuss their coding and to develop coding frames for the complete dataset. Having done so, AS and GH coded transcripts using an agreed coding frame and met again to verify coding. At each phase there were codes that were specific to participants'/families' experiences of living with BS. These codes included: Living with BS, Symptoms of BS, Treatment of BS, Child Development and Growth, Communication and Role of MDT, Social Functioning and Integration, View of Self, Schooling and BS, Social Support, Psychological Support for BS, Perceived Stigma and Normalisation, and Management and Coping Strategies. Once each coding frame was finalised, all the transcripts were imported into NVivo 12 and electronically coded.

Key themes
The analysts met again and endeavoured to reach consensus about how the individual codes informed the development of themes from within the dataset (Fig. 1). This process led to identifying 4 key themes: • Diagnosis and treatment • Social support • Identity and social integration • Symptoms and self-regulation

Diagnosis and treatment
Parents reflected on their sons' diagnosis of BS and knowledge at this time was important for parents to understand the condition as a syndrome-i.e. that the heart was not the only organ affected by the condition. They understood that BS could be life-threatening but were reassured by knowing their sons were getting the correct care: Parents became aware of individual differences in the symptomatology of BS and of the potential risks the condition might pose for their child in the future, such as the risk of heart failure. In addition, they were made aware of the extent that medication was managing the condition in the present and would be necessary throughout their lives: Even before they diagnosed the Barth syndrome, they said, "These drugs, he'll be on this for life." I was saying, "Do we have to stop them doing sports?" They said, "Oh, no, they can carry on doing sports as far as they're able," and this, that and the other, "They'll never be professional sportsmen, but they'll be on these drugs for the rest of their lives." (06, Phase 1, Father)

Social support
Individuals and families spoke of the emotional and instrumental support they received from knowing each other through the community, within the clinic and involvement in national and international support networks. An example of emotional support: There was also a temporal element so that some families felt support groups were more helpful in the early stages of diagnosis rather than the adolescent stage:

Identity and social integration
Parents were concerned that their sons should not be singled out on the basis of having BS. However, this could be paradoxical in that attempts at integration in school sports events and /or social activities could have a negative experience for boys if poorly managed: Furthermore, as sporting ability is strongly associated with social acceptance and integration in adolescence, a perceived lack by others of ability to compete was felt to be socially and psychologically damaging for some boys and resulted in a lack of inclusion: Barth  However, non-participation in sport could mean watching on the side-lines which could be disheartening for parents as well as the child:

He used to come home and say, about playing football-which is obviously why he hasn't got a big circle of friends-'I can't play football, they won't kick the ball to me. ' 'Well, no, you've got to train. ' He can't compete in that sort of… So, you don't know if it is because of
To watch football, yes. He would love to play, and I think that does have some psychological, emotional things for him. It also, I guess, has it for us as well in terms of looking and seeing that he wants to do something and he's physically not able to. So that's disheartening to an extent. (08, Phase 1, Father) The weakness and fatigue associated with BS due to compromised heart function could mark out boys in the school environment as they were more vulnerable to risk: So, if he gets knocked and it's… they're just kids brushing past quickly he's much likelier to tumble than anybody else. We make sure that he doesn't have to carry his school bag round because it would add extra fatigue with the weight, he could tumble again more. So, I'll always hand his school bag into his classroom. Little things…(011, Mother, Phase 1).
Another issue associated with fatigue was that it is poorly understood by others in their social environment and they are thus labelled as 'lazy': Because there are heart condition aspects, but my heart is stable and I'm doing okay, thankfully.

But, yes, fatigue-I'm tired all the time. It's difficult because everybody labels you as lazy and you don't want to do anything. I'm like, "Yes, because I'm tired. That's why I don't want to do anything. " (03, Phase 1)
Future oriented social integration was a cause for concern for parents and some had started to consider how their son's futures would look. As established friendships become more fluid, due to life changes and educational choices, the ability to initiate new friendships could present a challenge: There were also clinical and biological factors that some parents perceived would increase their child's risk of infection and imposed restrictions on large social events for their son with BS. In particular this was due to neutropenia and compromised immune functioning: He's neutropenic, so obviously that has a slight pressure on you because you do have to rethink things sometimes because you're not going to go into a place where it's thousands of people and go to a festival. You know that he could potentially pick something up, so you're a little bit more careful, but we try and do most things. (08, Phase 1, Mother)

Symptoms and self-regulation
Fatigue was a prompt for self-regulation. However, some boys expressed that their fatigue could be overwhelming: Parents were also aware that their child could challenge themselves with regard to onset of fatigue knowing they could be autonomous in their attempts at self-regulation: I think we try to be as normal with everything as we can, which in turn gets him to do more. So he challenges himself on quite a few things and even though he's tired he'll say, "Oh, can we rest for a bit?", and then five minutes later, "Right, let's go." So he does push himself. He doesn't wallow in self-pity, which is great, and he's just a delightful, focused little kid. All the challenges that you could have attributed to a condition like this, I think that he just goes past most of them on his own accord without being pushed or anything. (08, Phase 1,Father) Parents also thought that participation in social events could be managed but this had implications in terms of physical recovery: Yes, the energy cells so that you have, "Oh yes, you're great. You're doing fine," and then 'bang' . If you were playing rounders, you might do a one to one, so physically... If you're a kid at a sleepover, a couple of days later, you might be tired in that way much more. His coordination and recovery period are, yes, very different. The sleep was good. You can see the core-stability thing. You can know by a kid. (02, Phase 1, Mother) Some parents felt compelled to intervene in situations where the child was engaged in physical activity such as physical activity prescription schemes. The parents also encouraged their child to advocate for themselves: There also appeared to be a degree of day to day variation in energy but despite parental experience it could not be monitored within a known range: It's very up and down, I think, because there are times when he can participate a lot more than others. It's weird because I think, with the condition, you never know what you're going to get, day by day. It's not something that you know, "Okay, this is the benchmark, he's going to be able to walk 500 steps a day maximum, minimum 300" so you've kind of got a range to go with. (08, Phase 2, Father) Some behavioural coping strategies were endorsed by parents in the school environment to negate negative peer to peer and/or social comparison: He doesn't perceive himself as different from anybody else at all. He goes to a small school where they do horizontal age grouping, so the children within his school setting are from three and a half up to twelve. So, it's mixed age groups, so therefore he doesn't really perceive himself as any different to anybody else physically. (010, Phase 1,Mother) Discussion This is the first qualitative exploration of the experience of individuals born and living with Barth Syndrome (BS) from the perspective of adolescents, young adults and parents. The findings suggest that self-regulation and coping in boys with BS was interpersonal and contingent on parental awareness, such that parents were aware that their child had a limited energy reserve and that had to be managed due to the implications of fatigue for daily living. Furthermore, individual differences in the impact that these participants reported was rooted in the same set of symptoms (tiredness, weakness) although the level of impact was dependent on the level of perceived symptom severity.

Findings in context of previous research
The observations represent parental anxieties regarding their child's prognosis and long-term health, educational and vocational concerns. These findings also resonate with Jacob et al. [9] where parents of individuals with BS reported higher 'internalised' care-giver strain (e.g. negative feelings) compared to objective or 'externalised' strain (e.g. disruptions to daily life, such as schedule changes). However, an encouraging finding of the present study is that parents used adaptive rather than maladaptive coping strategies in response to their child's condition, such as acceptance, positive reframing, emotional support and instrumental support, which were manifested through inter-personal relations, support groups, and medical professionals. Furthermore, there was an observed inter-dependency, demonstrating that the management of BS is dependent on both adolescent and parents. Previous research has shown that the efficacy of adolescents' self-regulation skills in these interpersonal processes is driven by parental involvement and their level of knowledge, and is reflective of how adolescents involve their parents in disease management [13]. Indeed, research in the health behaviours of adolescents suggests that many self-regulation skills can be recast as both individual and interpersonal in nature. For example, adolescents must regulate their cognitive, emotional and behavioural responses to unrequested parental involvement in disease management and foster a sense of autonomy, which may lead to conflict [12]. However, there was little evidence of family conflict in the present data set suggesting that coping strategies were carefully implemented and demonstrated parent-child coherence that resonates with the findings of Williams et al. [8]. The present data also appear to support those of Storch et al. [4] in that self-regulation and psychosocial functioning in young people with Barth Syndrome is coherent within families; parents showed a high level of awareness of their son's limitations and the impact of BS on their school and social lives.
Qualitative research [15] found that, for adults living with BS, coping strategies included adapting daily routines, managing physical limitations and relying on social support networks. The present study found that the development of these skills in adolescents with BS is mediated by external forces; many boys were still developing emotionally and physically and within the structure provided by full-time education and family living. In the Mazar et al. study [15], participants reported that their symptom progression increasingly limited their physical functioning and independent living thus there is a need for greater awareness from others within the context of social and employment networks in the absence of family support. Finally, there are implications for care and future research arising from these qualitative findings such that it should be considered how coping strategies can be implemented for long-term role function, employability and independent living. These findings, from individuals below the age of 35, help to give psychosocial context to the natural history and progression of BS, and demonstrate the resilience of patients and their adaptation to BS.

Data quality and reflexivity
A strength of this study is that data was collected via interviews conducted at 2 time-points. This longitudinal approach optimised rapport and candour with participants and their parents over 5 months. Furthermore, the multi-perspective approach serves to better understand how adolescents, young adults and their parents experience BS within the context of family life. The density of the data and the consolidation of emerging themes suggest that data saturation was achieved.
The lead author and analyst (AS) has extensive experience of qualitative research in patients' experience of illness and engagement with health services but had no prior experience of BS or working within the NHS Specialised Services Barth Syndrome Service in the U.K. Similarly, the second data analyst (GH) is also an experienced qualitative researcher with no prior experience of BS or its treatment, which serves to enhance the robustness of the findings and minimises the risk of inherent bias.
From a historical and contextual perspective, it was important to patients attending the BS service that there was access to a playroom to act as a social hub where patients and parents could socialise whilst waiting for investigations and medical reviews. The MDT at the service also led teaching sessions about potential outcomes such as heart failure or neutropenia. This opportunity for socialising and learning served in providing cohesion between patients and families. In addition, previous clinics run by the Barth Syndrome Service were of longer duration, which facilitated greater face-to-face time with both medical professionals and with other families. However, smaller clinics were introduced, which increased discussion time with medical professionals but radically reduced the number of families attending on any 1 day, resulting in reduced contact with others in the Barth community. As a consequence, Barth Syndrome UK (the UK-based Barth Syndrome charity) has instigated an annual family weekend (where possible), one of which was held between the interviews at the two study timepoints. Therefore, during the time-period of the study, there was a high level of social and instrumental support and social integration, so the present study should be considered within this specific condition and treatment context. This was corroborated by a representative of Barth Syndrome UK (MD) who felt that the findings reported in this manuscript resonated with their experience of supporting families affected by BS.

Conclusion
The present findings suggest that self-regulation and coping with BS was interpersonal and contingent on parental involvement. Furthermore, parents were aware that their child had a limited energy resource that had to be managed due to the implications of fatigue for daily living. The findings also support previous quantitative work demonstrating that children and parents tend to share a coherent view of BS [7]. However, there is a need for greater awareness from others within the context of social and employment networks in the absence of family support which may have adverse implications for future life choices. With regard to family life these finding serve to validate parents who are sometimes made to feel neurotic and guide the transition process from boyhood to adulthood (for both parents and affected individuals). Furthermore, such knowledge can be used to educate teaching staff around various issues: accepting parents' involvement where appropriate, and helping young people to self-regulate and advocate for themselves. In addition, employers may use this knowledge as a resource to better understand the unpredictability and severity of fatigue and muscle weakness to accommodate affected individuals by providing flexible working/careers that are manageable, purposeful and enable them to transcend the limitations of a BS diagnosis.

Availability of data and materials
Data for this study was obtained from participants taking part in an NIHR funded clinical trial and the data cannot be shared on a publicly accessible data repository due to legal and ethical reasons. However, data will be made available for secondary research, conditional on assurance from the secondary researcher that the proposed use of the data is compliant with the with the UK Policy Framework for Health and Social Care Research and MRC Policy on Data Preservation and Sharing regarding scientific quality, ethical requirements and value for money. Please contact cardioman-trial@bristol.ac.uk to discuss any data requests. Data will be made available after the study has been closed and the primary publication is out. It will be made available indefinitely. Only data from patients who have consented for their data to be shared with other researchers will be provided.

Declarations
Ethics approval and consent to participate All participants were in a double blind, crossover, randomised controlled trial of the oral drug bezafibrate. Ethical approval for the qualitative interview study was granted as part of the clinical trial within which it was conducted (REC ref: 15/SW/0228) on 12/11/2015. The interview data formed the basis of evaluating trial participation and are under the care of the national NHS Specialised Services Barth Syndrome Service, which is based at Bristol Royal Hospital for Children.

Consent for publication
As part of the informed consent procedure all participants gave permission for their interviews to recorded for analysis and if necessary relevant data could be used for publication in an anonymised form.