Experienced fatigue in people with rare disorders: a scoping review on characteristics of existing research

Background Experienced fatigue is an under-recognized and under-researched feature in persons with many different rare diseases. A better overview of the characteristics of existing research on experienced fatigue in children and adults with rare diseases is needed. The purpose of this review was to map and describe characteristics of existing research on experienced fatigue in a selection of rare diseases in rare developmental defects or anomalies during embryogenesis and rare genetic diseases. Furthermore, to identify research gaps and point to research agendas. Methods We applied a scoping review methodology, and performed a systematic search in March 2020 in bibliographic databases. References were sorted and evaluated for inclusion using EndNote and Rayyan. Data were extracted on the main research questions concerning characteristics of research on experienced fatigue (definition and focus on fatigue, study populations, research questions investigated and methods used). Results This review included 215 articles on ten different rare developmental defects/anomalies during embryogenesis and 35 rare genetic diseases. Of the 215 articles, 82 had investigation of experienced fatigue as primary aim or outcome. Included were 9 secondary research articles (reviews) and 206 primary research articles. A minority of articles included children. There were large differences in the number of studies in different diseases. Only 29 of 215 articles gave a description of how they defined the concept of experienced fatigue. The most common research-question reported on was prevalence and/ -or associations to fatigue. The least common was diagnostics (development or validation of fatigue assessment methods for a specific patient group). A large variety of methods were used to investigate experienced fatigue, impeding comparisons both within and across diagnoses. Conclusion This scoping review on the characteristics of fatigue research in rare diseases found a large variety of research on experienced fatigue. However, the minority of studies had investigation of experienced fatigue as a primary aim. There was large variation in how experienced fatigue was defined and also in how it was measured, both within and across diagnoses. More research on experienced fatigue is needed, both in children and adults with rare diseases. This review offers a basis for further research. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-02169-6.


Study design
As reported by the authors Fatigue definition and focus on fatigue.

Was fatigue definition described in introduction?
Investigation of experienced fatigue primary or secondary aim/ outcome? Fatigue major or medium/ minor focus? Fatigue mentioned how many times? (review authors assessment)

Methods used for investigating experienced fatigue
Quantitative studies -Use of study-specific questionnaire? -Use of a standardized fatigue instrument? (Which instrument?) Qualitative studies -Individual interviews -Focus group interviews -Other qualitative methods?

RARE DEVELOPMENTAL DEFECTS/ ANOMALIES DURING EMBRYOGENESIS
Arthrogryposis Dai, S., et al. 2018 Disability in adults with arthrogryposis is severe, partly invisible, and varies by genotype France To understand the disability of adults with arthrogryposis multiplex congenita (AMC), a rare disease spectrum characterized by at least 2 joint contractures at birth in different body areas. 43 participants with AMC, 27 female, mean age 33.2.

Prevalence of fatigue
Retrospective study Fatigue definition not given Investigation of experienced fatigue one secondary aim Fatigue minor focus. Fatigue mentioned 4 times Study-specific. 4-day multidisciplinary evaluation. Fatigue assessed by a structured interview of psychological problems.

Congenital limb deficiency
Johansen, H., et al. 2018a Chronic pain and fatigue in adults with congenital unilateral upper limb deficiency in Norway. A crosssectional study Norway to: 1) Provide a further description of self-reported chronic pain, 2) Study the prevalence of severe fatigue, 3) Explore the associations between chronic pain and demographic and clinical factors and 4) Explore the associations between fatigue and demographic and clinical factors among adults with CUULD in Norway. 77 adults with congenital unilateral upper limb deficiency, 71% women, mean age 42.7 (20-82) Prevalence and associations to fatigue Cross-sectional survey Fatigue definition given in introduction: Fatigue is often defined as an "overwhelming sense of tiredness, lack of energy and feeling of exhaustion, mental, physical or both" (Dittner 2004) Investigation of experienced fatigue one primary aim Participants were parents (n = 45) of children with VCFS ages 2 to 18 years.

Prevalence of fatigue
Cross-sectional questionnaire study Fatigue definition thoroughly described in introduction: "Fatigue is defined clinically as a decline in performance during sustained activity, and can be associated with performance on both motor and cognitive tasks" (Schwid et al., 2003). Fatigue defined in introduction. The experience of fatigue (or subjective fatigue) has been described as a "an overwhelming sense of tiredness, lack of energy and feeling of exhaustion" that is "not relieved by rest" and is a common sequel of chronic conditions (Bleijenberg 2003;Karlsen 1999;Krupp 2003 Respondents rated from 1-4 if the symptom had "no impact," "minor impact," "moderate impact," or "major impact" on their life. Heatwole, C., et al. 2012 Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1)

USA
To determine the most critical symptoms in a national myotonic dystrophy type 1 (DM1) population and to identify the modifying factors that have the greatest effect on the severity of these symptoms. To determine the frequency and relative importance of the most life-affecting symptoms in myotonic dystrophy type 2 (DM2) and to identify the factors that have the strongest association with these symptoms.

The Netherlands
The aim of this qualitative study was to explore parents' perspectives on the impact of MFS on daily functioning of children with MFS aged 4-12 years, themselves and family regarding functional performance, activities, participation, personal and environmental factors, and disease burden.
N= 10 in individual interviews, and 3 focus groups (n = 5, n = 5 and n = 6). All participants were parents of a child with MFS aged 4-12 years.