Lifestyle program in treatment of Pompe disease. Combining exercise training and dietary intervention.

Glycogen storage disease type II is also known as Pompe disease. This is a rare
autosomal recessive disorder with a deficiency of lysosomal enzyme acid α-1,4-
glucosidase.This results in accumulation of glycogen mostly in cardiac,
skeletal and smooth muscle cells. Pompe disease displays a broad clinical
spectrum. Patients with the classic infantile subtype are severely affected
with hypotonia and cardiomyopathy from the first months of life. Without
treatment patients die within the first year of life due to cardiorespiratory
failure. Late onset Pompe disease varies in onset from early childhood to the
6th decade of life, if this is under the age of 18, it is also classified as
juvenile onset. Severity of the phenotype varies but all patients show
progressive muscle weakness with a limb-girdle distribution, and weakness of
respiratory muscles. Eventually, these patients become wheelchair and/or
ventilator dependent. Pompe disease is the first myopathy to be treated with
enzyme replacement therapy (ERT), which is implemented in 2006. This therapy
improves muscle strength, muscle function, and stabilizes respiratory function.
However, there is individual variation in response to ERT, targeting the enzyme
to skeletal muscles remains difficult and not all muscle damage is reversed.
Furthermore, other disease related factors influence the condition of Pompe
patients: first, at least in part related to physical inactivity and a
decreased resting metabolism, patients are often overweight. Fifty percent of
the Dutch Pompe patient population has a BMI >= 25.This overweight further
inclines mobility of the patients and negatively influences respiratory
function. Second, reduced mechanical forces on the skeleton, lowers the
patients* bone mineral density, predisposing to development of osteoporosis.
Third we found a higher incidence of hypertension and signs of increased
aortal stiffness in our patients. All these factors predispose patients to
cardiovascular disease and diabetes and all these factors may benefit from a
life style intervention. However, unaccompanied dieting or training by patients
with a myopathy may lead to increased loss of muscle mass. Therefore we think
personalized lifestyle programs, developed by a team specialized in Pompe
disease and lifestyle, comprising exercise training and dietary intervention
are strongly needed to complement enzyme replacement therapy.
Our team has already demonstrated improvement of cardiorespiratory fitness,
muscle strength and physical functioning from a feasible and safe training
program of 12 weeks in mildly affected Pompe patients. However, data on
efficacy and safety of a complete life style intervention are limited. Only
two previously published studies concern a lifestyle intervention comprising
dietary intervention and exercise, but both studies have major limitations
including a very small amount of patients and do not provide psychological
guidance. Our aim is to implement a personalized lifestyle program combining
exercise and dietary intervention, with psychological support, in the largest
population of late onset Pompe patients so far.

To determine the effect of a personalized lifestyle program on endurance,
muscle strength, muscle function, core stability, quality of life, bone mineral
density, body composition, energy expenditure, physical activity, muscle
morphology, respiratory function and metabolic state.

Interventional cohort study. First 12 weeks patients will maintain their usual
daily activities and intake. In the second 12 weeks patients start following a
personalized lifestyle program. Measurements are performed at the start, 12 and
24 weeks. When not on ERT, patients can start the lifestyle program without a
resting phase. When not on ERT the duration of the lifestyle program is 12
weeks.

Based on patients* energy requirement and physical ability to perform exercise,
a personalized lifestyle program will be made. Program duration is 12 weeks. A
combination of endurance, resistance and core stability training will be
implemented. Patients will exercise at a maximum of three times a week for 60
to 90 minutes per session at their local physiotherapy practices The dietary
intervention will be based on patients* BMI (underweight <18,5, normal
18,5-24.9 and high >=25) giving rise to respectively a hypercaloric, isocaloric
or hypocaloric feeding, which always consists of high-protein, low-carbohydrate
and normal fat content diet. A lifestyle coach will help the patients to adjust
their lifestyle to the proposed interventions.

The study requires a time investment of 24 weeks. Patients visit our outpatient
clinic for measurements at the start ,12 and 24 weeks (only at the start and 12
weeks when not on ERT). These measurements are distributed over two days,
meaning patients will visit our outpatient clinic on a total of 6 days (4 days
when not on ERT) during the program. Two of these days will coincide with their
regular outpatient clinic visits. Because an incremental exercise test could
affect another test outcome, two measurement days are required. The following
measurements are performed at our outpatient clinic: height, weight, abdominal
and hip circumference, skinfold thickness measurement; blood pressure
measurements; blood sampling; incremental cardiopulmonary exercise testing
(CPET) with measurement of gas exchange variables, 12-lead electrocardiography,
pulse oximetry, heart rate, and intermittent non-invasive blood pressure during
exercise, using a cycle; submaximal incremental exercise test with measurement
of gas exchange variables, 12-lead electrocardiography, heart rate, and
intermittent non-invasive blood pressure during exercise ; respiratory function
tests; muscle strength MRC and HHD; muscle function: timed tests and QMFT; core
stability tests; muscle biopsy (optional); MRI-scan of muscles (optional);
total Body DEXA-scanning; medical interview and physical examination by sports
doctor; nutritional assessment by a dietician with indirect calorimetry.
Furthermore, a psychologic assessment and guidance by a psychologist (optional)
will be implemented. In the weeks between measurements patients fill out
questionnaires, record their daily intake and wear an activity monitor at home
for 10 hours a day

Invasive procedures comprise blood sampling (3 samples at the start, 12 and 24
weeks (only 2 samples when not on ERT: at start and 12 weeks). and muscle
biopsy which is optional (needle biopsy of the quadriceps muscle, before and
after lifestyle intervention). These procedures could lead to pain, hematoma or
infection. However these interventions will be performed by trained personnel
following hospital protocols. Maximal incremental exercise tests could provoke
cardiac arrhythmias, these tests are secured by monitoring with continuous
electrocardiograms and frequent bloodpressures. Exercise training is performed
3 times a week, during 60-90 minutes. Training consists of endurance training
(tread mill or cycling at submaximal workload), resistance training (consisting
of repetitive exercises for arm and leg muscles, with or without weights,
during a maximum of three sets of 15-20 repetitions) and core stability
training with various planking exercises in accordance of patients* abilities.
Exercise could lead to muscle soreness and sports injuries. To prevent these,
patients are seen by a sports physician in advance of the program and guided by
physiotherapists at each training session. After each training session patients
will record their experience in a diary. Patients will follow a dietary
intervention (daily, during 12 weeks).The investigator will contact patients
weekly. Biweekly blood tests (1 sample) will be performed for safety
monitoring. This sampling will be combined with their regular biweekly
treatment through intravenous application of enzyme therapy. Dieticians and
psychologist will contact patients during the program to evaluate the adherence
and give guidance where needed.

Based on our previous experience in training mildly affected Pompe patients,
which was feasible and safe, we expect no major complications. We expect all
patients to benefit from a lifestyle program. Patients will be able to continue
training, dietary therapy, guidance by a dietician and a psychologist after
this study.