Living with Glutaric Aciduria Type 1: Experiences of Adolescents and Their Families Living in Germany

Objective: This study was conducted to investigate the effects of treatment of a child with glutaric aciduria type-1 diagnosis on the health-related quality of life of a child and his family via in-depth interviews. Methods: The study was conducted in qualitative research design in the pediatric metabolism department of a university hospital in Germany. The inclusion criteria of the study were as follows: a family 1) with a child followed up with glutaric aciduria type-1 and who was exposed to a (tryptophan and) lysine restricted-diet, 2) with other healthy siblings aged between 10 and 25 years, and 3) who agree to participate in the study. The study was carried out in the framework of a biopsychosocial-spiritual model with a child (n=4) who was followed up with glutaric aciduria type-1 and his family. A total of 10 interviews were conducted. The interview records were transcribed and analyzed. Results: In the study, 4 main domain and 11 themes were determined according to the biopsychosocial-spiritual model. The physical effects of the disease, the positive effects of treatment, and limitations were the themes in the biological domain. The psychological domain included themes named as psychological reactions to the disease, adaptation to the treatment process, coping strategies, and future concerns. The domain of social effects explained themes such as family and environment communication-interaction. In the spiritual domain included the meaning and objective of life and belief-values. Conclusion: Living with glutaric aciduria type-1 disease and treatment received was found to have multiple effects on the quality of life of children and their families.


INTRODUCTION
Glutaric aciduria type-1 (GA1) is a rare autosomal-recessive hereditary neurometabolic disease that is due to deficiency of glutaryl-coenzyme A dehydrogenase (1). The prevalence of the disease is 1 in 100,000. The estimated incidence in Germany is 1 in 112,700 newborns (2). GA1 requires lifelong treatment and monitoring. It is often accompanied by macrocephaly, encephalopathic crises during catabolism is a typical feature, symptoms such as delayed speech and motor development, permanent dystonia, and irreversible brain injury are often observed (3,4). Patients with GA1 suffer from mental retardation as well as emotional and behavioral problems. These symptoms affect all family members in addition to the child (5).
Hereditary metabolic diseases can affect intrafamilial interactions, social lives of parents, the interactions between spouses and other siblings, and may have a financial impact (6,7). Gramer and coworkers (8) stated that in metabolic diseases, especially in situations where the diet is important, the burden of care is high and burnout is frequent in affected families. The international guideline on GA-1 recommends that the psychosocial effects of diagnosis and treatment should be evaluated as part of routine follow-up in both affected individuals and their families (9).
The physical, social and psychological effects of chronic diseases on the life of the affected individual and his family, often has an impact on health-related quality of life (10). The perspective of affected families is very important in determining the experiences, needs, and expectations of families, especially in rare metabolic diseases. It is necessary to listen to all family members, especially young people in the family, to understand the effect of living with metabolic disease and receiving dietary treatment on health-related quality of life (11).
Only few studies on GA1 exist (12). There are no studies on the experiences and quality of life of families regarding the disease and treatment process. The present study is thought to address this gap in the field by focusing on the effects of the disease and treatment process and the opinions and experiences of young individuals. For this reason, this study was carried out to determine the impact of living with the diagnosis of GA1, which is a rare condition and a target disease of newborn mass screening in Germany using the tandem-MS technique. Diet and other treatments have an impact on the health-related quality of life of the patient and his/her family.

Theoretical Framework
Since chronic disease affects the individual in many aspects including biological, social, and psychological terms and also has an effect on the quality of life concept, our study employed the biopsychosocial-spiritual model. The theoretical framework and interview questions of the study were designed based on the biopsychosocial-spiritual model developed by Sulmasy (13). Figure 1 shows the form of the model as adapted to the current study. The questions prepared according to the model can be found in Appendix 1.

MATERIALS and METHODS
The study was carried out in the basic qualitative research design. The basic qualitative research design was thought to be appropriate for this study. The study used the purposive sampling method. The inclusion criteria of this study were as follows: a family 1) with a child who was diagnosed with GA1 and who was exposed to a (tryptophan and) lysine restricted-diet, 2) with other healthy siblings aged between 10 and 25 years, and 3) who agreed to participate in the study. Diagnosis of GA1 was based on clinical and neuroimaging findings and confirmed by blood tandem mass spectrometry (TMS) and/or urine gas chromatography and mass spectrometry (GC/MS) and/or genetic analysis. After all, there were 5 children with GA1 cared for in the paediatric outpatient clinic for inborn errors of metabolism at Hannover Medical School. The family included in the study met the inclusion criteria and were easy open to communicate about their situation. In the study, patient, mother, father, and sibling titles were used to keep the anonymity of individuals. The family was invited to read and sign a consent form permitting the interviews. No vote by the ethical review commission was required as the interviews were essential in the clinical context to define the outcome of disease.

Instrumentation and Procedures
In-depth, semi-structured interviews were held with the families who agreed to participate in the study (Appendix-1). The interviews were conducted by the first author. The family was informed about the study, and a consent form was obtained for their participation in the study. The first interview was held with the patient, who was followed-up in the outpatient clinic, and subsequently the mother, and the father as well as siblings (when applicable) were interviewed. The first meeting was performed in a quiet treatment room of the policlinic. During the interview, the speech, gestures, and mimics of the participants were observed by the researcher. Other interviews were conducted in a quiet room in the family's home. A total of 10 interviews including 3 interviews with the mother and father separately with one-week interval, and two interviews with each of the two children of the family. The interviews lasted approximately 30 minutes to an hour. The median interview time was 45 minutes in parents and 30 minutes in children. During the interviews, a voice recorder was used after the permission of the participants was obtained.
The framework of the biopsychosocial-spiritual model leading the interviews was as follows: • Physical effects of the disease, positive effects of the treatment, and limitations of the treatment were analyzed in the biological area. • The first psychological responses to the disease, compliance with the treatment and nutrition program, coping strategies, and future concerns were analyzed in the psychological field. • Intrafamily communication and interaction, and communication and interaction with the environment were analyzed in the field of social effects. • Understanding the purpose of life and the effect of belief/values were analyzed in the spiritual field.

Data Analysis
The content was evaluated by considering the thematic analysis steps developed by Braun and Clarke (14). Before starting the content analysis, the interviews in the audio recordings were first listened to and transcribed. The transcription of the audio records of the interviews was made by the researchers themselves to prevent data loss. Ten interview texts were reviewed several times by two researchers, and the researchers noted their impressions. The interviews, which were transcribed during the analysis, were coded sentence by sentence to have more comprehensible outcomes. A "code list" was created using the codedsentences data. Later, themes that could explain these codes under certain categories were identified. Similar codes were classified into clusters and then a table containing these themes was created to see these individual concepts, which were later organized in groups, and to observe the connections between each of them. For the validity of the data, the coded themes and statements were submitted to the opinion of an expert in the field. Figure 2 provides a summary of the main categories and emerging themes.

Participants
The child, who was followed up with the diagnosis of GA1, was 15 years old and attending a school for the physically disabled. He stated that he loved nature and animals very much. He said moving, running, and dancing were highly important for him. His elder brother, who was 17 years old, was a high school student and he was very interested in cars. The father was 41 years old, and the mother was 40 years old. The father worked in a cleaning company and the mother worked as an elderly care technician in a nursing home.

Effects of living with glutaric aciduria type 1 and the treatment program
The themes determined as a result of the interviews were illustrated in the field of the biopsychosocial-spiritual model. Since the parameters of the model have a dynamic structure in interaction with each other, some overlaps may have occurred in the sub-items of the themes (Figure 3). Figure 3: Biopsychosocial-spiritual model for living with glutaric aciduria type I

Biological effects
"I noticed that my child was different" Physical effects of the disease "On the day I gave birth, I said there was something wrong and weird with my child. My baby's head was very big and long. He did not cry. I had noticed something was wrong with my baby" (The Mother). "My child started walking and talking at the age of four. When he started walking, he constantly fell to the ground. His knees and head were always in sores. The wounds on his knees never disappeared" (The Father).
"Nutrition plan and medical treatment was our hope" Changes and benefits coming with nutrition and medical treatment: "Nutrition was important for my child. What foods contained lysine and tryptophan and what did I need to give him? The nutritionist taught them to me. My child recovered when he paid attention to his diet (The Mother). "Child development teachers suggested animal therapy to better use the energy of our child and to speed up his speech. We went horse-riding for two days a week. My child's speech improved. It healed my child. We still continue horse-riding" (The Father). "Diet compliance alone may sometimes be inadequate". Limitations of the Treatment Program: "We paid attention to my child's diet, but he seemed as if he did not have much strength. I searched for the issue a lot, and I found articles claiming that vitamin support would be good. Then, multivitamin support was added to his treatment. After the vitamin supplement he received with his special formula, my child revived, recovered" (Mother).
"It was forbidden to give fish and meat derivatives for the first 6 years. It was our chance to apply not only the nutrition program, but also the combination of occupational therapy, speech therapy, work-activity, and animal therapy" (Father).
Psychological Effects "When I first heard it, I was totally wrecked; I was shocked." The first reaction of the family to the disease: "I felt all my world got wrecked when the chief physician of the district hospital where I gave birth said my child had a problem… We learned that our child had a rare disease ... When I first heard it, I was shocked" (The Mother).
"I was preparing to take my wife and baby to our house. My wife told me that our child was sick ... I couldn't accept it, I was in shock ... I accused my wife of what has happened to us, telling her that it was because of her concerns" (Father).
"Our first six years were like a horror movie." Compliance with nutrition and medical treatment: "We are a family that loves eating meat. My child is unable to eat meat because of his diet. The dietitian said that we should not eat meat near the child … and that the child should get used to this situation. She told us to eat the meat and give the bone to the child. I resented it so much; I was so sorry" (The Mother).
"People around us often accused us by asking how we ate in front of our child and how we tolerated this situation. It was a very difficult situation for us. It was difficult, but we got used to it" (The Father).
"Running away this process or keep going". Coping strategies: "My child was sick ... I was thinking if there was a need to go to ergo therapy, speech disorder unit. I thought those in Europe and my wife were exaggerating it. I walked away from my family for a while; I ran away ... I could not cope" (The Father).
"I was ready to welcome all kinds of difficulties. I accepted it. The doctor said we were lucky to diagnose it early, and I even evaluated it as good news… Because I was a mother; I had to continue for my child" (The Mother).
"When I noticed my brother's illness, I was not aware of the situation much. He was different, but everyone loved him. For a while, I pretended as if there was no such disease. I used to join my friends when they made fun of my brother. But now I think much differently (The Brother). "I have concerns" Future concerns: "I do not think that he will be able to protect his property and money in the future. If somebody asks for the 100 Euros he has, he gives it" (The Mother).
He is a child who can be fooled easily. He doesn't want to break anyone's heart.... I have concerns ... After five years of working, Germany gives my son a chance to retire. I know that my child will not depend on anyone, even without us. However, there must be someone who will support him, who will love him like his mother, father, or wife (The Father). "My brother is a pure and friendly person. Therefore, he can be fooled. I can predict what may happen in the future. As his elder brother, I will protect him from now on; I will guide him" (The Brother).

Social Effects In-Family Communication and Interaction
"Changes when we were separated and when we were together with my husband". Communication between spouses: "I neglected myself and my husband so much. I gained 60 kilos at once. I was badly-groomed. My husband and I were separated for a while because he did not understand me at the beginning. When we came over our problems with my husband, we had considerable progress in our child's illness" (The Mother).
My wife and I have collaborated against challenges later, though we could not do it at first. I have tried to alleviate her burden because she worked.
As partners, we have succeeded it together, and we continue our struggle (The Father).

"Continuity of communication with the health professionals is very important" Communication with the health professionals:
The doctor and dietitian were vitally important to us… I investigated a lot of things. I shared what I found with the doctors; they supported me (The Mother).
Continuity of communication with the healthcare professionals was very important. We got support. If there had been someone available at the beginning for managing and directing everything, things would have been easier for families (The Father). I have talked to religious people to ask for prayers… I was more focused on faith and beliefs, especially at the time of the first diagnosis. My child's illness had a major impact then. Turning to religion and faith relieved me especially in the early days of the process (My Father).

Biological Effects
The family mentioned the importance of diet in the treatment of the child, and they said they observed developments in the child when the diet was applied. In GA1, a lysine-restricted diet and amino acid-formula (with lysine-free, low tryptophan content) are important to support adequate growth and development as well as preventing metabolic crises and encephalopathy (15). In our study, the family mentioned that they attached great importance to carnitine supplementation and diet to support the child's growth and especially brain development. However, the carnitine and micronutrient approach in the treatment of GA1 is based on a few cross-sectional studies and reports of some case studies in the literature. Evidence-based studies for medical treatment of patients followed-up with the diagnosis of GA1 are needed (15).
The family in our study reported that the diet regimen supported their quality of life to some extent, and that treatment was more effective with multiple treatment approaches such as speech and language therapy, and animal therapy. Liégeois and Morgan reported that it was important to start speech therapy in children with metabolic disease, which is responsible for 76% of speech disorders (16). The treatment approach found in the literature was observed to coincide with the treatment approach that the child and the family were directed in our study. However, after evaluating the child in GA1, we noticed that evidencebased studies were needed regarding the treatment and therapy approaches that families could be directed to.

Psychological Effects
In our study, the parents stated that they were shocked when they first heard the diagnosis after birth. In the literature, the moment when families first learn the diagnosis is depicted as the most difficult time to bear (17). The mother had a rapid transition to the acceptance stage with her maternal instinct and taking on the care responsibility. The father, on the other hand, showed reactions in the form of accusing the mother and moving away for a while. In the literature, the perceptions of society regarding the roles of the mothers and fathers are also effective. When the differences between fathers and mothers in terms of reactions to chronic diseases are examined, studies can be seen to generally focus on mothers as the mother is the main caregiver and the father is mostly engaged in financial affairs (18,19). The existence of evidence-level studies that will determine the differences between the mother and father is important in terms of eliminating the gap in the field (18,20).
Family members may have difficulty coping with the time-consuming care and different medical and dietary treatments of the patient (17). In our study, the father reported that several treatment methods were administered and he tried to get away from the disease process for a while as he could not cope with it.
Also, the mother mentioned that she spent efforts for her child with her maternal instinct, she suppressed some emotions to cope and tried to be strong. Similar to our study, Golfenshtein et al. (21) stated in their study that mothers tried to be strong by suppressing their emotions for their children in cardiology intensive care and that they coped with it in this way.
In genetically hereditary metabolic diseases, the mental state of the individual is affected (22). Individuals with mental retardation can make up a group that believes others readily and is open to neglect and abuse. For this reason, parents' concerns for the future increase in these situations (23). In our study, the family thought their child believes everyone and can be easily fooled because he could not do calculations for simple monetary matters. In the literature, it is seen that families with children who are followed up with the diagnosis of metabolism have concerns about how their children live in adulthood, the conditions that may be experienced in transition to independence and their safety (12,24). In chronic diseases, parents' concerns about their children's future affect their quality of life.

Social Effects
Taking/giving care to a child with hereditary metabolism disease affects the marriage relationships, the development of other siblings, and the relationship with other people around them (10,25). In our study, the mother stated that she focused her attention on her sick child more and that this affected the relationship between the spouses. In the study of Pelentsov et al. (19) most of the parents whose children were followed up with a rare disease mentioned that the disease process brought the spouses closer to each other, while some parents stated that the mother was often busy with caring the child and that the father worked for earning money, which prevented parents from spending time together (19).
In social communication and interaction, communication with nature and animals has positive effects on the development of children. In our study, the family stated that being in touch with nature and doing gardening made the child realize what he could do and that therapy with animals such as horse riding speeded up the child's speech. Studies have reported that these therapies support the development of the child and increase psychological well-being in children with speech delay (26), children with mental disabilities (27), and children with cerebral palsy (28). The combination of approaches such as animal therapies and medical therapy in neurometabolic diseases are thought to provide progress in the treatment and growth of the child.

Spiritual effects
In life-threatening situations, the patient and the family increasingly need spiritual resources such as hope, inner confidence, empowerment, loving and being loved, harmonious relationships, religious practices, relationships, and seeking meaning (29,30). The mother in our study reported that she made sense of her child diagnosed with glutaric aciduria as her miracle and that she found happiness in life with this perspective. The mother stated that the process shaped the meaning and purpose of life. The father added that the meaning and purpose of life came from being healthy, and so he understood it better. In our study, the other sub-themes discussed in the spiritual dimension of the disease were "my beliefs and values". The mother mentioned that her belief in what she could do as a caregiver facilitated the process rather than religious belief. The father, on the other hand, mentioned that embracing his religious belief gave hin relief in the early stages of the diagnosis. In the study of Büssing et al. (31) the effects of the disease process on spiritual needs in individuals with diseasecausing cancer and chronic pain was studied in Germany in four areas. These included religious needs (praying, attending a religious ceremony, reciting religious/spiritual books, etc.), need for inner peace/tranquility (desire to be in a place where you will find silence and peace, experiencing the beauty of nature, talking to someone about fear and anxieties), and existential needs (31).

CONCLUSION
GA1 affects the quality of life of the patient and the family in many ways. According to the results of the study, it is important to know the factors affecting health-related quality of life to be able to plan and implement an appropriate approach to the family and child followed-up with this diagnosis. One of the limitations of the study was that it was conducted with a small sample size. On the other hand, holding an in-depth qualitative interview with the family constituted the strength of the study.