Fatigability is a frequent phenomenon in spinal muscular atrophy (SMA). However, there is a lack of scales designed for and validated in SMA patients to determine the frequency and impact on daily life of physical fatigue and perceived fatigability in these patients.
Material and methods
This is an observational cross-sectional study in a cohort of patients older than 14 years with genetically confirmed SMA. We used a new questionnaire ( PROfuture ) designed to assess physical fatigue and perceived fatigability, and classified patients with SMA according to their functional status as non-sitters, sitters, and walkers .
Fifty-one patients completed the questionnaire. More than half of them reported symptoms of physical fatigue, although the frequency and type of symptoms varied between functional groups. Non-sitters reported a greater impact of physical fatigue on daily activities, while walkers more frequently presented fatigue associated with overexertion. Regarding perceived fatigability, non-sitters reported it most frequently when performing activities that involve the upper limbs and axial muscles, followed by sitters . Walkers presented high perceived fatigability in the lower limbs, but lower severity in the upper limbs.
Physical fatigue and perceived fatigability in patients with SMA are very frequent and affect activities of daily living. Therefore, their assessment should be included in the routine follow-up of these patients. A holistic approach to the fatigue–fatigability phenomenon in SMA is essential to understanding its pathophysiology and achieving an adequate therapeutic management.
La fatigabilidad es un fenómeno frecuente en la atrofia muscular espinal (AME). Sin embargo, no disponemos de escalas validadas y diseñadas para AME que nos permitan medir la frecuencia y repercusión en la vida diaria de la fatiga física y la fatigabilidad percibida en estos pacientes.
Material y métodos
Estudio transversal observacional en una cohorte de pacientes mayores de 14 años con AME con confirmación genética utilizando un nuevo cuestionario ( PROfuture ) para determinar la fatiga física y la fatigabilidad percibida. Los pacientes se clasificaron según su funcionalidad en non-sitters, sitters y walkers.
51 pacientes completaron el cuestionario. Más de la mitad presentaban algún síntoma de fatiga física, aunque la frecuencia y tipo de síntomas variaron según el grupo funcional. Los non-sitter son los que refieren un mayor impacto de la fatiga física en las actividades diarias (37–75%), mientras que los walkers presentan una mayor sensación de cansancio asociado a esfuerzos. Respecto a la fatigabilidad percibida, los non-sitter registran una mayor frecuencia en actividades que implican a miembros superiores (74–100%) y musculatura axial (67–78%), seguidos de los sitters (22–95%). Los walkers presentan elevada fatigabilidad percibida en miembros inferiores (67–87%), pero escasa en los superiores (17%).
La fatiga física y la fatigabilidad percibida por los pacientes con AME son síntomas muy frecuentes y afectan a actividades básicas de la vida diaria, por lo que deberían evaluarse en el seguimiento rutinario de los pacientes. Una aproximación holística al fenómeno fatiga-fatigabilidad en la AME es esencial para entender su fisiopatología y realizar un adecuado abordaje terapéutico.
Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease caused by a homozygous deletion and/or mutation of the SMN1 gene, and affects the lower motor neurons almost exclusively. Although weakness and progressive muscular atrophy are the most frequent symptoms of SMA, fatigue and fatigability are also frequent and potentially disabling manifestations. However, these are frequently overlooked in current clinical practice. This is due to the lack of a standardised concept of these phenomena, which has hindered the study and general understanding of symptoms, the development of diagnostic methods, and the implementation of specific therapies.
First, we should distinguish between fatigue and fatigability. , Fatigue is defined as perceived mental and physical exhaustion that interferes in daily living activities. This is a subjective symptom and, therefore, may only be identified using questionnaires assessing its severity and impact on daily life. Fatigue may be further subdivided into several categories, mainly mental and physical fatigue. The assessment of physical fatigue is especially relevant in SMA, as it is the type expected to be most strongly associated with the pathophysiology of the disease and thus to respond to specific treatments. , ,
Fatigability is the clinical sign that characterises the decrease in physical performance over the duration of a task. , , In SMA, fatigability manifests as a result of the instability of the neuromuscular junction. Therefore, it is assessed using physical tests involving the repetition of tasks using submaximal strength, such as the Six-Minute Walk Test, the Nine-Hole Peg Test, or the Endurance Shuttle Walk Test. , , Although these tests enable us to determine the presence of fatigability, they do not reflect its real impact on the activities of daily living. This gives rise to a need to assess perceived fatigability, understood as a variant of the physical dimension of fatigue that reflects the impact of decreased motor performance on the activities of daily living. ,
Furthermore, drug regulators recommend using patient-reported outcome measures (PROM) to assess the positive impact of different treatments on patients’ lives.
There is currently no specific, validated tool for assessing symptoms of physical fatigue and fatigability in patients with SMA. In this study, we aimed to describe the frequency of symptoms of fatigue and perceived fatigability in order to determine their impact on activities of daily living and to conduct a preliminary analysis of a new, ad hoc questionnaire.
Material and methods
This is a descriptive, cross-sectional study based on patients’ responses to the “Fatiga y Fatigabilidad” (Fatigue and Fatigability) scale designed by the FundAME Foundation. The scale is part of the PROfuture questionnaire, which is included in a patient registry ( wacean.com/registroame ) developed and promoted by FundAME, , which published the questionnaire online and collected users’ responses. These data were subsequently provided for analysis and interpretation by the neuromuscular diseases unit of Hospital Universitari i Politècnic La Fe.
We included the responses of patients with SMA who met the inclusion criteria and completed the questionnaire between 1 May and 30 November 2020.
We included patients with a genetically confirmed diagnosis of the disease (5q13 chromosome alteration consisting of homozygous deletion or mutation of the SMN1 gene), aged 14 years or older.
Exclusion criteria were not signing the informed consent form or not having completed at least half of the questionnaire.
Four patients were excluded from the study based on these criteria.
We recorded the following variables: age, age at symptom onset, type of SMA, functional classification, genetic study, number of SMN2 copies, maximal motor milestone achieved, wheelchair use, surgery for scoliosis, specific treatment for SMA, feeding by percutaneous endoscopic gastrostomy or nasogastric tube, and use of non-invasive mechanical ventilation.
The items included in the scale may be consulted in the supplementary material. Questions refer to the presence of these symptoms over the past 7 days. Questions on physical fatigue address 5 aspects: need to rest during the day, need to select activities, difficulty in maintaining posture, loss of energy over the course of the day, and presence of prolonged tiredness after making a greater effort than usual. In the section on fatigability, participants are asked about the inability to finish a task once started, referring to activities of daily living that require sustained and repeated use of the upper limbs (taking written notes, sending text messages, combing the hair, brushing the teeth, and eating without help), axial muscles (sitting up straight, holding the head upright), and lower limbs (climbing a flight of stairs, walking at a steady pace, standing up from a chair or bed, getting in or out of a car). Therefore, participants unable to initiate the task did not respond to the corresponding item.
After the preliminary review of the results, we decided to eliminate item no. 8 (*) from the “Perceived fatigability in upper limbs and axial muscles” section, given the low number of responses received.
It should be noted that the “Physical fatigue and endurance” section initially had 5 possible answers (never/almost never/sometimes/nearly always/always) and the “Perceived fatigability” section had another 5 options (impossible/very difficult/difficult/somewhat easy/easy). We decided to group answers in 3 categories (never or almost never/sometimes/always or nearly always) in the “Physical fatigue and endurance” section and 4 (impossible/difficult or very difficult/a bit difficult/easy) in the “Perceived fatigability” section, with the aim of facilitating the interpretation of results, as some options were rarely selected.
With the data obtained, we performed a descriptive analysis using the mean (standard deviation) and median (percentiles 25 and 75) of quantitative variables, and the frequency (percentage) of qualitative variables.
Some results are represented as graphs to facilitate their interpretation. Graphs were plotted using the Excel software, version 19 (2018). Statistical analysis was performed using the R statistics software (version 4.0.5).
The sample included 51 patients with SMA, with a mean age (at the time of completing the questionnaire) of 31.9 years (SD: 13.92). Median age at symptom onset was 15.5 months. By functional classification, our sample included 16 non-sitters (31.37%), 20 sitters (39.22%), and 15 walkers (29.41%). Almost half of the patients (47%) reported following a specific treatment. The demographic and clinical characteristics of the sample are shown in Table 1 .
|Mean (SD)/n (%) |
|Age (years)||31.9 (13.92) |
|Mean age at symptom onset (months)||37.92 (54.49) |
|Functional classification: |
|Type of SMA: |
SMA type 1
SMA type 2
SMA type 3
SMA type 4
|SMN2 copies |
|Highest motor milestone achieved |
Standing or walking a few steps with the help of a third party or a device
Remaining seated independently
None of the above
|Motor function of the arms and hands |
I can lift my arms above my head
I can bring my hands to my mouth
I cannot bring my hands to my mouth but my hands do have useful motor function
I have no motor function in the hands
|Use of wheelchairs |
No, I do not use one
|Specific treatment |
|Surgery for scoliosis |
|Genetic study |
Deletion of both copies (in homozygosis) of the SMN1 gene
Deletion of one copy and point mutation of the other copy of the SMN1 gene
After external review by experts from Hospital Universitari i Politècnic La Fe, the questionnaire was considered to present content validity and to be adapted to the functional status of patients with SMA. Furthermore, it refers to relevant activities of daily living, such as hygiene, feeding, and communication. However, one question was excluded from the “Perceived fatigability” section (referring to the fatigability in the upper limbs during games) due to the low response rate. Furthermore, the activities proposed in this section (brushing the teeth, combing the hair, writing, etc) may not adequately reflect perceived upper limb fatigability in walkers, as they require little effort. We should also highlight the fact that the third item on physical fatigue, which assesses patients’ limitations in maintaining posture throughout the day, includes a question on an issue that is already adequately addressed in the “Perceived fatigability in axial muscles” section; thus, its inclusion in this section is redundant. Likewise, with a view to facilitating the interpretation of results, we opted to remove some of the options that were selected infrequently, as the variety of options did not lead to better understanding of the SMA phenomenon.
Results in the “Fatigue and fatigability” section, according to functional capacity
Overall, 84% of patients with SMA reported some symptom of physical fatigue, with the need to select activities (52%), and loss of energy over the course of the day being the most frequent (52%). On the other hand, the need to rest was the least frequent (39%).
Fig. 1 presents the responses according to functional group. As can be seen, physical fatigue manifests unevenly between functional groups, with non-sitters and walkers being more frequently affected (87%) than sitters (80%). However, the most frequent symptoms vary considerably between groups. Thus, compared to other groups, non-sitters more frequently needed to rest during the day (item 1) and to select activities (item 2) and presented greater difficulty maintaining posture (item 3) and a greater sensation of loss of energy (item 4) at the end of the day.