Safety and efficacy of exercise training in adults with Pompe disease: evalution of endurance, muscle strength and core stability before and after a 12 week training program

Patients

Patients were recruited at the Centre for Lysosomal and Metabolic Diseases, Erasmus
MC University Medical Centre, Rotterdam, the Dutch national referral centre for patients
with Pompe disease.

There were three inclusion criteria:

1. A confirmed diagnosis of Pompe disease measured by decreased acid ?-glucosidase
activity in leukocytes or fibroblasts, and mutation analysis;

2. Age??17 years;

3. Treatment with ERT for at least 52 weeks

There were four exclusion criteria:

1. The use of walking-aids or a wheelchair;

2. Ventilator-dependency;

3. Concurrent medical conditions;

4. Participation in other exercise-training programs.

The study was approved by the Ethical Committee at Erasmus MC University Medical Centre.
Informed consent was obtained from all patients.

Study design and intervention

Three times a week for 12 weeks, all patients followed a standardized training program
that was provided under the supervision of physical therapists at carefully selected
sports or fitness centres near the patients’ homes. To ensure the uniformity of the
program and its supervision, all therapists attended a one-day instruction program
at Erasmus MC University Medical Centre. The training program is depicted in Fig. 1. The first training session was on-site supervised by one of the researchers from
Erasmus MC (LvdB, MF), who subsequently attended each training site every two weeks
to monitor proper conduct of the program.

Fig. 1. Flowchart for the standardized exercise-training regime combining aerobic, resistance
and core stability exercises

Patients were randomly subdivided into two groups: group 1 (n?=?13), which started the training program at week 1; and group 2 (n?=?12), which started at week 13. The staggered start of training allowed us to investigate
whether any improvement observed in the training period could also be attributed to
ERT. Furthermore, the duration of the effect of the training program can be evaluated
from the follow-up of patients in group 1 after they stop training in week 12.

To assess the effects of the program, each patient visited our centre (Erasmus MC)
on two separate days in weeks 0, 12 and 24. The primary endpoints of this study were
safety, endurance and muscle strength. Secondary endpoints were core stability, muscle
function, and body composition.

Under the supervision of the physical therapist, training diaries were kept by all
patients, who recorded the days on which they trained, the weight and number of repeats
of resistance exercises, and the perceived level of exertion. To evaluate training
progress and patients’ motivation, patients were telephoned weekly.

Assessments

Safety

Plasma CK was measured every two weeks as a safety marker for exercise-induced muscle
damage 12], and patients were contacted every week to record potential side effects such as
pain and fatigue.

Endurance

Aerobic (endurance) exercise capacity was determined using an incremental cycle ergometer.
After 4 min of unloaded cycling on the cycloergometer (Jaeger ER 800; Erich Jaeger,
Würzburg Germany) exercise intensity was increased progressively until exhaustion
(i.e. ramp protocol), during continuous measurement of patients’ heart rates and ventilator
parameters using spiroergometry equipment (Oxycon Pro, Jaeger, Würzburg, Germany).
The rate of increase was determined considering the patient’s functional capacities
and ranged from 5–20 Watts/minute. The duration of every individual test exceeded
6 min but did not take longer than 12 min. At exhaustion, the rating of exertional
symptoms was assessed using the Borg scale (scale 6–20) 13], patients consistently scoring 14 or above. Maximum workload capacity (W
_MAX
) and, peak oxygen uptake capacity (VO
_{2 PEAK}
) were measured. The ventilatory threshold (VT) was assessed independently by two
clinical exercise physiologists using the ventilatory equivalents method 14]. The test was considered to be maximal when one of the following criteria was met
14]:

1. heart rate??90 % of that predicted,

2. respiratory exchange ratio (RER)??1?·?11, or

3. VO
₂
stabilized despite increased workload.

Walking distance on the 6-min walk test (6MWT) was evaluated according to the American
Thoracic Society guidelines.

Core Stability

To assess the dynamic balance, which reflects core stability, one physical therapist
(MF) measured time in balance (in seconds) for each of the four core stability exercises
of the training program (Fig. 1) 15].

Muscle strength

Muscle strength was assessed by one investigator (SW) using Hand-held Dynamometry
(HHD). Assessments were performed in a standardized manner, and sum scores were calculated
as described previously 6].

Muscle Function

Functional activity assessments comprised three timed tests: 10 meter running, climbing
four steps, and rising from supine to standing positions 16], and the Quick Motor Function Test (QMFT), a test specifically designed and validated
for Pompe patients 17]. The QMFT consists of 16 specific motor skills related to daily activities. A total
score is achieved by summing the scores for each item (ranging from 0 “cannot perform”
to 4 “can perform with no effort”), and is expressed as a percentage of the maximum
score.

Body composition

Bone-mineral density (BMD) and body-composition measurements were performed conform
DXA technology using a Lunar DPX densitometer and analyzed with Encore 2002 software
(GE Lunar DPX, GE Health Care). Bone densitometry was performed in a standardized
manner as described previously 18]. Body composition was described in terms of the mineral, lean and fat body mass (kilograms).
The percentage of fat mass and, more specifically, android and gynoid fat, were calculated.

Statistical analysis

Patient characteristics were summarized using descriptive statistics. Data for the
two groups were combined after verifying that there were no significant differences
between outcome measures before the start of the training (group 1 – week 0; group
2 – week 12; student’s t-test for normally distributed, and Mann–Whitney for not-normally
distributed data).

Mean differences before and after the training were compared using the paired t-test
for normally distributed data, and otherwise the Wilcoxon signed rank test for paired
samples. For group 2, we also used these tests to compare the outcome measures before
and after 12 weeks of ERT only (week 0 to 12).

Significance level was set at p??0?·?05. Statistical analyses were performed using SPSS for Windows (release 17?·?0;
SPSS, Inc., Chicago, IL).