INTRODUCTION AND PURPOSE
Mitochondrial diseases are a clinically heterogeneous group of rare metabolic diseases. The prevalence in the Netherlands is 1:5000.1 Mitochondrial diseases are caused by genetic mutations in the mitochondrial or nuclear DNA.1,2 These mutations interfere with the functioning of the mitochondria, cell organelles that facilitate the production of energy in the cells. This genetic disorder results in a defect in the mitochondrial respiratory chain, which uses oxidative phosphorylation to produce adenosine triphosphate, the energy currency of the cell.2 Because mitochondria are present in almost every cell of the body, the results of defects of mitochondrial function are multisystemic. They can result in a wide variety of symptoms such as exercise intolerance, muscle weakness and cramps, diabetes mellitus, ptosis, and deafness.1 Because of their high metabolic requirements, muscle and brain tissue are mostly affected.2 When the skeletal muscles are the most affected, the disorder is called mitochondrial myopathy (MM). Currently, a definitive treatment for mitochondrial diseases has not been established. The present therapy consists mostly of supportive care such as physical, speech, and occupational therapy.3,4 Very little research has been done on the management of MM, especially concerning nonpharmacological treatment options. A systematic review by Cup et al5 in 2007 described level II/III evidence (classification of the Dutch Institute for Healthcare Improvement)6 for the positive effect of strengthening and aerobic exercises in neuromuscular diseases in general, including MM. During the past decade, several studies have examined the effect of aerobic exercise programs on MM.7–9 Although these studies had a small number of participants and most lacked control groups, all studies showed a positive effect on aerobic exercise capacity, activity of the mitochondrial respiratory chain, and quality of life.7–14 However, all these studies involved adults. The general positive effects of physical activity for children (prevention of cardiac diseases, development of coordination, and self-esteem) are well known.14 For children with neuromuscular diseases in general, there are very few well-designed controlled training interventions. Some evidence exists supporting the value of exercise for these children, suggesting that maximal aerobic power, muscle strength, and O2 cost of locomotion are sensitive to training in children with neuromuscular disease.15 Although MM is a neuromuscular disease, no studies focusing on physical activity and training specifically for children with MM could be found.
Experience shows that for children with MM finding a balance between physical exercise and rest is difficult. To avoid symptoms of muscle pain and fatigue, the natural reaction of the children and their social environment is to reduce the amount of physical activity. But inactivity can lead to a negative spiral of reduced exercise capacity and an earlier onset of symptoms. This dilemma leads to questions concerning the optimal amount of exercise for these children and how this can be monitored. To be able to answer these questions, the present activity of children with MM in relation to children who are healthy needs to be known and which measurement tools are suitable to measure the physical activity of children with MM. The first purpose of this study was therefore to compare the physical activity of a group of children with MM with that of children who are healthy with the same characteristics (sex and age). The second purpose was to evaluate different tools for measuring physical activity in children with MM.
Because of the lack of literature on the level of physical activity in children with MM, the study had an explorative observational design. The study was divided into 3 parts: a day of observation, a week of measurement with accelerometry, and 2 questionnaires. The study was executed during the spring and summer of 2009.
Children were included in the study group if they had the diagnosis of MM with normal intelligence or mild retardation (IQ > 60, according to Wechsler16), were between 8 and 12 years of age, and were going to a regular primary school or a school for children with disabilities affiliated with a rehabilitation center. Children were excluded if they were wheelchair-bound or otherwise physically limited in movements during the study (eg, a fracture), had serious behavioral problems, or had other diseases interfering with the study and physical activity (eg, cardiac conditions).
The control group consisted of children who are healthy, between 8 and 12 years of age, who did not have health problems interfering with the study. The children were selected to have an equal distribution of sex and age.
The Ethical Review Board deemed this study did not meet the requirements of medical research with subjects and therefore did not need to be assessed by the Board. In accordance to Dutch laws, all parents and children of 12 years or older signed an informed consent.
Observation of Physical Activity
During one school day (approximately 6.5 hours), the physical activities of the children were observed and recorded with event logging software (Observer XT 8.0.330, Noldus Information Technology, Holland; see Figure 1). This software can be used to code data according to predefined activity types (eg, sitting and running) and the duration of these activities. Employing recorded video data of the school day, Observer XT was also used to code the data afterwards. The observation day was chosen to include guided exercise activities: a gym class or physical therapy (for the children with MM). All possible types of activities during the observation day were divided into 3 intensity categories on the basis of energy expenditure.17,18 This resulted in the following categories: light (MET < 3 and/or VO2 < 11 mL/kg/min), moderate (MET 3.0-6.0 and/or VO2 11.0-24.5 mL/kg/min), and high/vigorous activity (MET > 6.0 and/or VO2 > 24.5 mL/kg/min). The categories of moderate and vigorous activity were combined as moderate to vigorous physical activity (MVPA).19–21 The results of the observation were the percentage of the observed time and the absolute time spent in the specified categories.
Heart Rate Monitoring
The children wore a heart rate monitor (Wearlink RS400sd Multi, Polar, Finland) that stored the heart rate every 5 seconds while being observed. Afterwards, the following data were derived: the mean heart rate during the observation period; the estimated individual aerobic threshold (according to the Karvonen formula)22; the percentage of time during the observation day when the heart rate was above the aerobic threshold (matching moderate to vigorous activity)22; and the mean heart rate for each physical activity intensity level. The heart rate was linked to the corresponding activity at each moment in the Observer XT software (see Figure 1). Heart rate monitoring was used because of the linear relationship between heart rate, oxygen consumption, and energy expenditure.19,21
Rate of Perceived Exertion
To gather information about the way children experienced physical activity, they were asked about their rate of perceived exertion 3 times a day (before the school day, after the lunch break, and at the end of the school day) using the Pictorial Children's Effort Rating Scale (P-CERT) (see Figure 2).23 The P-CERT is a valid test23 and superior to the Borg scale for children.24 For this study, the scale was translated into Dutch.
To measure the activity pattern for a longer period, the children wore an accelerometer during 7 consecutive days. The accelerometer (tri-axial Aktometer V3, ADXL330, Analog Devices) uses a piezoelectric sensor, which measures accelerations in 3 directions. Every 2 minutes it saves an activity score derived from the acceleration data of the preceding 2 minutes. This score is expressed as counts per unit time. During the test week, the children kept a diary of the descriptions of their activity with the help of their parents and teachers. The mean activity level, only during waking hours, was calculated per day and per week. Furthermore, the mean activity level was calculated separately for the week and weekend days.
Diary: Level of Fatigue
In their diary, the children also noted their level of fatigue using smileys (see Figure 3). The smileys had a rate from 1 (not tired at all) to 5 (very tired). The children with MM were acquainted with this method because it was used during their physical therapy sessions. The mean smiley scores were calculated during the week and per day (week and weekend separately).
Modifiable Activity Questionnaire
The Modifiable Activity Questionnaire (MAQ) is a questionnaire that gives information about physical activity during the previous year. This questionnaire has proved to be a valid and reliable instrument for the measurement of physical activity in children.25 The MAQ consists of 5 questions. The first 4 questions provide information about the number of days of the past 2 weeks the children performed light or hard activity, the number of hours per day the children watch television, and the number of competitive sports activities in which they participate. The last question collects information on activities in the past year reported by the children and their parents. With a formula described by Aaron et al,25 the average number of hours of activity per week for the past year was calculated. Not included were activities such as gym class, cycling/walking to and from school, and occasional activities (eg, skiing). For this study, a Dutch version was used, which has not yet been validated.
Handicap Scale for Children With a Chronic Illness
The Handicap Scale for Children (HSC) with a chronic illness measures 5 dimensions: mobility, physical independence, daily activities, social integration, and orientation.26 Each dimension includes a 6-point rating scale. For example, “some children are not completely healthy or they can't do as much as is usual. That means they can't get everywhere they want. How about you? Not at all (I can get wherever I want) to completely (I can't get out of bed or a chair),” according to Detmar et al.26 In the article by Detmar et al,26 the HSC has been described in detail. Using the formula developed by Van Dommelen et al,27 a total score for quality of life can be measured. A higher score indicates higher social participation. On the basis of an initial evaluation, Detmar et al26 found the questionnaire to be feasible and valid for use with children in the age range of 8 to 18 years. The parents were instructed to let the children complete the questionnaire themselves as much as possible. The questionnaire has been developed and validated in Dutch.26
Descriptive statistics were performed using the software package SPSS (version 11.5), Observer XT software, and Aktometer V3 software. All statistical analyses were performed using SPSS 11.5. Because of the small numbers of participants, nonparametric tests were used. Differences between the 2 groups were analyzed using the Mann-Whitney U test (for continuous variables) and the chi-square test (for categorical variables). Because of the small numbers, the exact P value according to SPSS was used for both tests. An α-level of less than 0.05 was considered significant.
Sixteen children were included, of which 6 had MM. See Tables 1 and 2 for the descriptions of the study group. To include more children with MM in the study, the age limits for the children with MM were extended to 7 to 13 years. The 2 groups of children were comparable considering the age, sex, height, and resting heart rate (Tables 1 and 3). The children with MM had a higher mean weight and significantly higher body mass index (22.1 ± 2.4 vs 16.6 ± 1.2; P = .000). Two boys in the healthy group were brothers, and 2 children in the MM group were brother and sister.
Observation and Heart Rate Monitoring
Most of the observed time (MM 78.4% ± 5.3 vs no MM 73.9% ± 3.8) the children performed sedentary activities, such as sitting and standing still. A significant difference was found between the time in MVPA: 71.4 ± 5.6 minutes per day for the children with MM compared with 88.0 ± 18.7 minutes for the children who are healthy; P = .042 (Table 3 and Figure 4). The difference between the 2 groups emerged specifically during gym classes and breaks. The children with MM did not participate in the regular gym classes at school and had lighter activities or even slept during breaks, whereas the children who are healthy played outside. Two of the children with MM did not have any guided physical activity on the day of observation.
The mean heart rate during the observed time, the resting heart rate, and the individually calculated aerobic threshold (according to the Karvonen formula)22 were comparable between the 2 groups (see Table 4). The percentage of time with the heart rate above the aerobic threshold showed a significant difference between the 2 groups. In absolute time, this was 6.2 ± 11.3 minutes (MM) compared with 14.3 ± 7.1 minutes (children who are healthy), with P = .042.
Rate of Perceived Exertion
There was a significant difference in fatigue during the whole day, with a higher level for the children with MM. The children with MM rated their mean fatigue at 4.2 ± 1.3 points, whereas the children who are healthy rated 2.6 ± 0.6 points (P = .007). The biggest difference was seen at the end of the school day, with 5.7 ± 0.8 versus 2.6 ± 1.4 points (P = .001).
Accelerometry and Diary
The children who are healthy had a significantly higher mean activity level than the children with MM during the week they wore an accelerometer: 93.4 ± 27.3 (MM) versus 125.1 ± 20.2 (no MM), P = .042 (see Table 5). The biggest difference between the 2 groups was seen during the weekend days. The mean rates of fatigue (recorded with smileys from 1 to 5) were significantly higher for the children with MM. This was found for both weekend days and weekdays as well as during the entire week. The children with MM gave a mean score of 3.1 ± 0.4 points, and the children who are healthy gave a mean score of 2.1 ± 0.4 points (P = .002).
Physical Activity: MAQ
The first 4 questions of the MAQ consist of 5 choices. Because of the small study group, not all possible answers were used. For the purpose of statistical analysis, some categories were merged. For questions 1 and 2, the categories “none” and “1 to 2 days” were merged and “6 to 8 days” was merged with “9 or more days.” For question 3, “none” and “1 hour” were taken together and “4 to 5 hours” was merged with “6 hours and more”.
Question 1 showed a significant difference between the 2 study groups: the children with MM had fewer days with “hard” activities than the children who are healthy (P = .030). The children with MM did not participate in sports on a competitive level at all, which resulted in a significant difference (P = .007). The number of days of light activity and hours of watching television did not differ between the groups. The total score for physical activity showed a trend toward a higher score for the group of children who are healthy with a mean of 5.7 ± 5.6 hours versus 1.1 ± 1.2 hours per week for the children with MM (P = .056).
Quality of Life: HSC
The HSC consists of 5 questions with 6-choice answers. As with the MAQ, not all answer possibilities were used, and for the purpose of statistical analysis, some categories were merged: “a little bit” with “pretty much” and “very much so” with “almost completely” and “completely.”
In all categories, except for social integration, a significant difference between the 2 groups was found. The children with MM reported a higher level of impairment. The biggest difference was seen in the category of physical independence. Three of the 6 children with MM had a high score for impairment, whereas 8 of the 10 children who are healthy had a low score. The mean total score (a higher score indicates a higher social participation) was 0.62 ± 0.14 for the children with MM and 0.86 ± 0.05 for the children who are healthy, which is a significant difference (P = .002).
To date there have not been any studies to examine physical activity of children with MM. With different measurement tools, this preliminary study showed that the group of children with MM was less physically active than the group of children who are healthy. The children with MM also reported a higher level of fatigue. One of the findings from the observation is that during the day the children with MM had a different activity pattern compared to the children who are healthy. For example, some of the children with MM did not participate in a gym class or physical therapy, because it is generally felt that this would cause too much strain for them. This has an influence on the outcome of the level of activity during the day and is one of the reasons for the difference between the 2 groups. The activity level during the observation was however a reflection of their normal activity level: all of the children with MM usually do not participate in the gym class at school and most of them stay inside during breaks.
The children with MM had a heart rate above their individual aerobic threshold for a shorter period, which indicates a lower intensity of physical activity. The heart rate as a measure of physical activity was chosen because of the linear relationship between heart rate, oxygen consumption, and energy expenditure.19,21 Whether this is the same for the children with MM is unknown. For adults with MM, however, a study showed a significant relationship between heart rate, plasma catecholamine, and lactate, and that there is the same elevation of the heart rate compared with adults who are healthy.28 Recently, Taivassalo et al29 published a study that describes vascular changes of the muscles in patients with MM, which affect the circulation and may have an effect on the relationship between heart rate and physical activity. This interesting finding has to be accounted for in the physiology of physical activity with patients with MM. This emphasizes the need of further research of the physiology of physical exertion in MM, especially for children.
The results of the accelerometer suggested that the difference between the groups should be found in leisure time: the children with MM had a lower accelerometer score over the whole week than the children who are healthy, especially on the weekend days. The large variations in the accelerometer scores for the group with MM can be explained by the large variation in the presentation of MM between individuals.
Besides the differences found in short term measures (observation) and medium term measures (accelerometry), this study also showed a difference in physical activity during the long term. According to the MAQ, the children with MM had “hard” activities on fewer days and did not participate at all in organized sports. The total score of the MAQ showed a difference in the total hours of physical activities per week (based on the previous year).
Even with this small study group and relatively mildly affected patients (not wheelchair bound and going to a regular school or school for children with disabilities instead of living in an institutional setting), significant differences were demonstrated in the level of physical activity and fatigue between the children with MM and the children who are healthy. The cause of these differences is uncertain: the children with MM may be fatigued earlier because of the shortage of energy production in the muscle cells (physiologic),28 or the cause may be of a more psychological nature: the children and their social environment may be afraid of overexercising and the adverse effects that may follow. The cause could also be a combination of both of these factors.
The second purpose of the study was to evaluate different tools for the assessment of physical activity in children with MM. From this study, the accelerometer and heart rate monitor seemed to be suitable tools. Both are small devices with minimal inconvenience for the children and are inexpensive and easy to use.19,21,30
Accelerometry is an objective, practical, accurate, valid, and reliable method to examine the amount and intensity of physical activity in children.20,30,31 In this study, both accelerometry and heart rate monitoring showed a difference in activity of children with MM compared with children who are healthy. A drawback of the accelerometer used in this study is the relatively long sample interval of 2 minutes, because physical activity of children is characterized by short bursts of intense physical activity.17 However, Reilly et al20 have concluded that although the widespread perception is that short intervals are essential, there is limited evidence for this and shorter intervals are mainly of interest when there is a focus on vigorous physical activity. Because in this study a combination of MVPA was used, it is assumed that the short sample interval did not have a great influence on the outcome.
When using a heart rate monitor, note that the physiology of children with MM is possibly different than the physiology of children who are healthy. Other useful measurement tools were the P-CERT and smileys to assess fatigue. These methods were understandable for the children and the P-CERT was easy to use in daily practice. The diary was less practical because the task for the children, parents, and teacher to keep notes for a week was intensive. The HSC is a short questionnaire for the quality of life, which was easy to complete, mostly by the children themselves. Because of its short character, it can be used, for example, during an intake with the rehabilitation physician or physical therapist.
On the basis of experience in this study, the MAQ and observation were less suitable measurement tools. The MAQ (especially the last question) seemed to be difficult to complete correctly by parents and children, and the mean score was highly variable. Because of these reasons, the total score of the MAQ was less representative although it gave a clear indication of the difference between the 2 groups.
Observation using software to register physical activities is a very time-consuming method,19 both the observation itself and the processing afterwards. Another disadvantage is that observation is always subjective, but, in contrast with the other measurement tools, it does give information about the specific types of activities besides intensity and amount of activity and it is does not require equipment that can hinder the children in their movements.19,21
Eventually 16 children were included, 6 with MM. Because the diagnosis of MM is rare, it was not feasible to include more children in this study. The small study group was the most important limitation of this study. Nevertheless, the results gave clear indications of a difference in activity between the 2 groups that can form a basis for future research.
In this explorative study, several measurement tools were used to evaluate the physical activity of children with MM. Validated tools for this population of children were difficult to find. Therefore, nonvalidated measurement tools were also used.
Heart rate monitoring is validated in children19,21 and also in children with cerebral palsy,32 but not specifically for children with MM. Although the Karvonen formula, used to estimate the aerobic threshold, is not validated for children, no alternative was available. The HSC is validated for use in children.26 Accelerometry is generally validated for use in children,20,30,31 but not the specific type of accelerometer used in this study. Although the smileys were not validated, they seemed to be very useful and are already used in daily practice. The MAQ and P-CERT are validated instruments for use in children,23,25 but validation was not repeated after their translation into Dutch.
Although not all the used measurement tools are validated, they are considered to provide enough support to the conclusions of this preliminary study. In future research, more validated measurement tools should be used (if available) and there is a need for validation of feasible instruments for this specific group of children.
The results of this study can serve as a base for future studies with larger groups of children with MM. Studies on adults with MM already show a positive effect from exercise training.7–13 The effect of exercise training programs for children with MM on their level of physical activity, health, and well-being can be evaluated using, for example, heart rate monitoring and accelerometry. Eventually, the development of a feedback system on the basis of the measurement of physical activity using the above-mentioned tools might help to find the balance between exercise and rest, which is a practical problem in daily life for these children and their social environment.
This exploratory study indicates that the children with MM in this study engage in less physical activity than children who are healthy. This was demonstrated with different measurement tools and in different time frames. Besides shorter periods and the lower intensity of their physical activities, the children with MM report a higher level of fatigue and a lower quality of life than the children who are healthy.
Heart rate monitoring, accelerometry, the P-CERT, smileys, and the HSC seemed to be suitable and easy measurement tools for the assessment of physical activity, level of fatigue, and quality of life in children with MM. Observation and the MAQ were less suitable tools.
1. Smits BW, Smeitink JA, van Engelen BG. Mitochondriële ziekten; orgaanspecialisme-overstijgend denken gevraagd. Ned Tijdschr Geneeskd. 2008;152(42):2275–2281.
2. McFarland R, Turnbull DM. Batteries not included: diagnosis and management of mitochondrial disease. J Intern Med. 2009;265(2):210–228.
4. Chinnery P, Majamaa K, Turnbull D, et al. Treatment for mitochondrial disorders. Cochrane Database Syst Rev. 2006;(1):CD004426.
5. Cup EH, Pieterse AJ, Ten Broek-Pastoor JM, et al. Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review. Arch Phys Med Rehabil. 2007;88(11):1452–1464.
6. Kwaliteitsinstituut voor de Gezondheidszorg CBO. Evidence-Based Richtlijnontwikkeling. Handleiding Voor Werkgroepleden. Utrecht: Kwaliteitsinstituut voor de Gezondheidszorg CBO; 2007. Appendex A1-4 Levels of evidence. www.cbo.nl/Downloads/632/bijlage_A.pdf
. Accessed April 16, 2013.
7. Taivassalo T, De Stefano N, Argov Z, et al. Effects of aerobic training in patients with mitochondrial myopathies. Neurology. 1998;50(4):1055–1060.
8. Taivassalo T, Shoubridge EA, Chen J, et al. Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Ann Neurol. 2001;50(2):133–141.
9. Jeppesen TD, Schwartz M, Olsen DB, et al. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain. 2006;129(Pt 12):3402–3412.
10. Taivassalo T, De Stefano N, Chen J, et al. Short-term aerobic training response in chronic myopathies. Muscle Nerve. 1999;22(9):1239–1243.
11. Taivassalo T, Gardner JL, Taylor RW, et al. Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions. Brain. 2006;129(Pt 12):3391–3401.
12. Cejudo P, Bautista J, Montemayor T, et al. Exercise training in mitochondrial myopathy: a randomized controlled trial. Muscle Nerve. 2005;32(3):342–350.
13. Trenell MI, Sue CM, Kemp GJ, et al. Aerobic exercise and muscle metabolism in patients with mitochondrial myopathy. Muscle Nerve. 2006;33(4):524–531.
14. Edouard P, Gautheron V, D'Anjou MC, et al. Training programs for children: literature review. Ann Readapt Med Phys. 2007;50(6):510–519, 499–509.
15. Bar-Or O. Role of exercise in the assessment and management of neuromuscular disease in children. Med Sci Sports Exerc. 1996;28(4):421–427.
16. Wechsler D. Wechsler Intelligence Scale for Children (WISC-III). 3rd ed. London: The Psychological Corporation; 1991.
17. Bailey RC, Olson J, Pepper SL, et al. The level and tempo of children's physical activities: an observational study. Med Sci Sports Exerc. 1995;27(7):1033–1041.
18. Ridley K, Ainsworth BE, Olds TS. Development of a compendium of energy expenditures for youth. Int J Behav Nutr Phys Act. 2008;5:45.
19. Sirard JR, Pate RR. Physical activity assessment in children and adolescents. Sports Med. 2001;31(6):439–454.
20. Reilly JJ, Penpraze V, Hislop J, et al. Objective measurement of physical activity and sedentary behaviour: review with new data. Arch Dis Child. 2008;93(7):614–619.
21. De Vries SI, Pronk MG, Hopman-Rock M, et al. Assessing Physical Activity in Children and Adolescents: A Review of Different Methods. Leiden: TNO Prevention and Health; 2004.
22. Takken T, van Brussel M, Hulzebos HJ. Inspanningsfysiologie Bij Kinderen. Houten: Bohn Stafleu van Loghum; 2008.
23. Yelling MR, Lamb KL, Swaine IL. Validity of a pictorial perceived exertion scale for effort estimation and effort production during stepping exercise in adolescent children. Eur Phys Educ Rev. 2002;8(2):157–175.
24. Marinov B, Mandadjieva S, Kostianev S. Pictorial and verbal category-ratio scales for effort estimation in children. Child Care Health Dev. 2008;34(1):35–43.
25. Aaron DJ, Kriska AM, Dearwater SR, et al. Reproducibility and validity of an epidemiologic questionnaire to assess past year physical activity in adolescents. Am J Epidemiol. 1995;142:191–201.
26. Detmar SB, Hosli EJ, Chorus AM, et al. The development and validation of a handicap questionnaire for children with a chronic illness. Clin Rehabil. 2005;19(1):73–80.
27. Van Dommelen P, Schulle A, Detmar M, et al. Preference-based measure of social participation from the Handicap Scale for Children. Expert Rev Pharmacoecon Outcomes Res. 2008;8(3):309–317.
28. Siciliano G, Renna M, Manca ML, et al. The relationship of plasma catecholamine and lactate during anaerobic threshold exercise in mitochondrial myopathies. Neuromuscul Disord 1999;9(6–7):411–416.
29. Taivassalo T, Ayyad K, Haller RG. Increased capillaries in mitochondrial myopathy: implications in for the regulation of oxygen delivery. Brain 2012;135:53–61.
30. Rowlands AV. Accelerometer assessment of physical activity in children: an update. Pediatr Exerc Sci. 2007;19(3):252–266.
31. De Vries SI, Van Hirtum HW, Bakker I, et al. Validity and reproducibility of motion sensors in youth: a systematic update. Med Sci Sports Exerc. 2009;41(4):818–827.
32. Rose J, Gamble JG, Meideiros J, et al. Energy cost of walking in normal children and in those with cerebral palsy: comparison of heart rate and oxygen uptake. J Pediatr Orhop. 1989; 9(3):276–279.
children; fatigue; female; human; male; mitochondrial disease; physical activity; quality of life