Tuesday June 24, 2014 Dr. Linda van den Berg received her PhD on 'The Musculoskeletal System in Pompe disease - Pathology consequences and treatment options' at the Erasmus University Rotterdam.
All patients with Pompe disease suffer from muscle weakness, which can ultimately lead to wheelchair use and artificial ventilation. Since its registration in 2006, enzyme replacement therapy (ERT) is the only treatment available for patients with Pompe disease. Although the availability of ERT has changed patient's perspectives in terms of improved survival, increased muscle strength and stabilisation of pulmonary function, not all patients respond equally well, and not all muscle damage and functional impairment is resolved.
The studies described in this thesis explore the muscle pathology in Pompe disease across the clinical spectrum, the interplay between skeletal muscle dysfunction and bone structure and the effects of ERT on it, as well as the use of exercise training to further improve patients' functioning.
Type of Muscle Fibers
In the thesis a case is presented of a patient with non-classic Pompe disease with a rather unusual clinical presentation of severe fatigue and myalgia (muscle pain) prior to the development of limb-girdle weakness. In this special case fiber type involvement was restricted to the type 1 muscle fibers. With this case report attention is raised to the occurance of fiber-type-specific pathology in Pompe disease, which was studied in a larger group of patients. Overall, patients with Pompe disease have the same muscle fiber-type distribution as healthy persons, except that patients in an advanced stage of disease seem to have a greater proportion of type 2x muscle fibers. As other researchers also noticed it is impossible to quantify the differences between the muscle biopsies of severely affected and less affected patients, despite the fact that there are clearly differences when visually inspected. These findings emphasize the need for appropriate and sensitive technologies for the routine follow-up of patients and for investigating the effects of ERT.
Bone Mineral Density (BMD)
Bone Mineral Density (BMD) was systematically assessed in a cohort of 46 patients, before the start of ERT using DXA technology. Low BMD, a possible indicator of osteoporosis as co-morbidity, was found to be common in patients with Pompe disease. At particular risk of developing this trait are children and patients who are wheelchair-bound and ventilator-dependent. However, in ambulant patients we also found low BMD. The low BMD of patients with Pompe disease correlates with decreased proximal muscle strength. The outcome of this study signifies the importance of screening for decreased BMD in all affected children, wheelchair-bound and ventilator-dependent adults and in all adults with progressive loss of muscle strength. With ERT eliciting a positive effect on skeletal muscle strength, it might also improve the BMD and influence body composition.
The effect of ERT on the BMD and body composition was investigated in 35 adult patients with Pompe disease. It was discovered that they had a lower lean body mass than healthy individuals; which is most likely due to their decreased muscle mass. Classification of patients according to either body mass index (BMI) or fat mass index (FMI) gave different results: 3 patients were classified as obese according to the BMI in contrast to 13 patients according to the FMI. In clinical practice the fat mass index (FMI) should be used preferably, since calculation of the BMI underestimates the fat mass of Pompe patients. No clinically meaningfull improvement in BMD nor body composition was observed within 2-3 years of ERT despite increase in muscle strength.
Exercise training in addition to ERT is explored in order to improve patients' fitness and physical functioning. A standardized and well-structured exercise intervention program combining aerobic, resistance and core stability exercises was followed by 25 patients three times a week for 12 weeks. Two patients did not complete the training program because it was too time-consuming for them. This left 23 patients, who successfully completed the study. In the thesis the effect of the combined training program on pain, fatigue, activity and participation was studied. It was shown that the program is feasible and can be performed safely by mildly affected patients with Pompe disease. As intended, such training helps to improve endurance, muscle strength, muscle function and core stability. The training program significantly improves fatigue and pain, and tends to improve mental health. It does not affect body composition, the quality of motor function nor the volume of physical activity. The observed improvements in pain and fatigue are not determined by aerobic fitness, muscle strength or core stability. This training program thus seems to offer added value for Pompe patients receiving long-term ERT.