Introduction
Pompe disease (OMIM #232300) is a rare neuromuscular disorder caused by deficiency of the lysosomal enzyme acid α-glucosidase. This deficiency induces glycogen to accumulate in the lysosomes of many tissues, albeit mainly in skeletal muscle. Its major clinical manifestation is progressive muscle weakness, which eventually impairs motor and respiratory function (van der Ploeg and Reuser
2008; Engel and Hirschhorn
1994). The disease manifests across a spectrum of severity, and affects infants, children and adults (van den Hout et al.
2003; Winkel et al.
2005; Kishnani et al.
2006). Patients with the classic infantile form present with severe generalized hypotonia and a hypertrophic cardiomyopathy shortly after birth; the disease progresses rapidly, and the patients usually die in their first year of life from cardiorespiratory failure. Childhood, juvenile, and adult forms of the disease are characterized by a more slowly progressive proximal myopathy. Respiratory muscles are affected as well. In these patients, onset of symptoms, disease severity and rate of disease progression varies. Cardiomyopathy rarely occurs. The majority of patients eventually become wheelchair and respirator-dependent (Hagemans et al.
2006; Laforet et al.
2000; Wokke et al.
1995).
In our centre we follow more than 100 children and adults with Pompe disease. The disease severity of these patients shows large differences. Some are ambulant and others completely wheelchair dependent. Currently there is no functional scale that has been standardized for Pompe disease and is capable to rate differences in muscle function sufficiently. This has become even more important since marketing approval was given to recombinant human alpha-glucosidase as enzyme replacement therapy for Pompe disease.
The aim of the present study was to construct a functional motor scale specific for Pompe disease that is easy to apply and sufficiently sensitive to assess disease severity and to detect clinically important changes over time, so that it can be used both in clinical practice to monitor disease progression and to evaluate therapeutic effectiveness. For this purpose, we constructed and psychometrically tested the scale in a large cohort of children and adults with Pompe disease.
Discussion
This study shows that the Quick Motor Function Test is a reliable and valid test for assessing motor function in patients with Pompe disease. It is the first muscle function test designed and validated specifically for Pompe patients. The test had good psychometric properties, including good internal consistency, and good intrarater and interrater reliabilities over the entire test and the separate items. The QMFT score strongly correlated with proximal muscle strength as measured by HHD and MMT, and significantly differentiated between patients with different levels of mobility. The test was evaluated in patients between 5 and 76 years of age, and was easy and quick to administer.
According to the World Health Organization, assessment of health should have a multi-dimensional approach. The International Classification of Functioning, Disability and Health (ICF) (World Health Organization
2001) provides such an interdisciplinary framework and measures consequences of disease in three domains: impairments of body functions and body structures, activity limitations (individual level), and participation restrictions (societal level).
In Pompe disease, the approach towards evaluating disease severity and effect of treatment has become increasingly multi-dimensional over the past years. Measurement tools have been designed and validated for their use in Pompe patients. Currently, a battery of tests is used in the long-term follow-up of Pompe patients. For example, muscle strength, pulmonary function tests, echocardiography, timed tests and the 6-minute walk test are used to evaluate disease consequences and effect of treatment on the level of body functions and body structures. The Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI), SF-36, and the Rotterdam Handicap Scale are used to assess the level of participation restrictions and quality of life. However, a validated tool to measure activity limitations on an individual level is currently lacking.
In clinical practice, muscle
strength tests have often been applied to assess muscle
function. However, although closely related, muscle strength and muscle function represent two different entities of the muscle system, and correspond to different levels of the ICF (World Health Organization
2001). Both parameters should therefore be evaluated separately by valid and reliable assessment tools.
In a recent placebo-controlled clinical trial in 90 juvenile and adult patients with Pompe disease, primary outcome measures were the 6 minute walk test (distance walked in 6 minutes), and Forced Vital Capacity in seated position (van der Ploeg et al.
2010). Muscle function was not assessed, because a reliable motor function test validated for Pompe disease did not exist. Although it would have been possible to use scales that were designed for other neuromuscular disorders (Russell et al.
1989; Main et al.
2003; Scott et al.
1982; Lovell et al.
1999; Berard et al.
2005) or a composite disease severity score that covers various domains of the ICF, as developed by Lue et al. for Duchenne Muscular Dystrophy (Lue et al.
2006), none of these scales were validated for Pompe disease. Some were designed for children, while Pompe disease affects all age groups. Our study demonstrates that the QMFT can be used in both children and adults, with different levels of disease severity.
Another quality of the QMFT is that it is easy and quick to perform. The test takes approximately 15 minutes, does not require specialized equipment, and can be performed by a physician in a clinical setting. As opposed to other scales, that frequently need to be performed by a physical therapist. It is a practical tool that can be used in all patients including those who are confined to a wheelchair or dependent on artificial ventilation. The overall responsiveness of the QMFT appears to be good: the test accurately detected change when it had occurred and remained stable when no change had occurred. It also discriminated between varying levels of disease. This indicates that the QMFT can serve as a tool to estimate disease severity, but also as a longitudinal assessment tool to detect changes in motor function over time. This is useful, as the emergence of new treatment modalities such as enzyme replacement therapy and possibly chaperone therapy will make the (long-term) evaluation of therapeutic effects essential.
Four issues need further attention. First, while responsiveness to change, which was assessed in a subgroup of 18 treated and 23 untreated patients, showed promising results, it is recommended to perform a large scale empirical study. The current study was insufficient to demonstrate whether the changes observed over time were related to enzyme replacement therapy or not. Second, the test was validated for patients between 5 and 76 years of age. In the youngest and oldest patients, motor development and age-related motor limitation might have interfered with the test results. Therefore, reference values for age should be obtained. Third, to ensure tester reliability we recommend annual recertification of the physicians who perform the QMFT. Fourth, the present study validated the QMFT in Pompe patients, but the test may also be useful for other neuromuscular disorders, especially those with proximal muscle weakness.
In conclusion, this study shows that the Quick Motor Function Test has good psychometric properties and excellent clinical utility. Our findings indicate that this test can be used to assess motor function and response to treatment in children and adults with different levels of disease severity. The applicability of the test for other neuromuscular disorders deserves further investigation.
Acknowledgements
We would like to thank S.P.M. van Schie, A.A.M. Zandbergen, and W.F.M. Arts for their contribution to the study, A.J.J. Reuser for critical review of the manuscript, and T. de Vries Lentsch for layout of the graphs. A copy of the test and user manual can be obtained via
www.pompecenter.nl.