Characteristic clinical features and pattern of muscle weakness
Our study in 94 adults with Pompe disease – which included virtually all known adult patients in the Netherlands – shows that, generally speaking, muscle weakness typically fits a pattern of limb-girdle myopathy. Interestingly, our findings about the distribution of muscle weakness, based on clinical examinations, match those of CT and MRI studies.
[24–26] We found weakness of the quadriceps muscle in 55% of patients only. This may have been due to our method of measuring muscle strength: whereas the advantage of the MRC score and HHD lie in the fact that they are easy for the clinician to use, quantitative muscle testing using QMT
[13, 27] may be more reliable in patients with only minor loss of strength.
Besides limb-girdle weakness, many patients had less familiar features, which are sometimes symptomatic of other neuromuscular diseases. Though ptosis has been reported in the literature in no more than seven adult patients to date
[28–31], it was found in almost one quarter of our patients. Notably, while one might expect myogenic ptosis to be bilateral, it was unilateral in two-thirds of our patients.
Despite the fact that bulbar muscle weakness is reported only occasionally in adult Pompe patients
[28, 32], twenty-eight percent of the patients in our cohort had distinct bulbar muscle weakness. These patients are at risk of pulmonary complications.
One third of patients had prominent scapular winging, which is in line with several recent reports
[32, 33]. Many of these patients also had bulbar muscle involvement and severer weakness of the shoulder-girdle muscles than patients without scapular winging; these features are reminiscent of FSHD. If patients with such a “pseudo-FSHD” phenotype are overlooked, diagnosis may be delayed. However, the asymmetrical distribution of muscle weakness, the relatively common involvement of the distal muscles of the lower limbs, and the absence of severe or relatively severe pulmonary involvement in FSHD will generally allow the two diseases to be diagnosed correctly
Serum CK activity was normal in 10 patients, confirming that a normal serum CK does not rule out Pompe disease
[35–37]. In early stages of the disease, however, normal serum CK is quite uncommon. Although we did not systematically perform electromyography or muscle biopsies, it is well known that these may reveal no or only non-specific abnormalities in a considerable number of patients
[38, 39]. Therefore, measurement of acid α-glucosidase activity and mutation analysis remain essential to confirm the diagnosis.
Natural disease course
Although the average follow-up duration of 19 months seems rather short for a chronic disorder such as Pompe disease, it is the longest prospective follow-up ever carried out in “late-onset” Pompe disease. Moreover, as many patients are now treated with enzyme replacement therapy, prospective data on the natural course of the disease over a longer period of time are now impossible to obtain.
We found a significant worsening of muscle strength, reflected by declines in MRC sumscore (mean decline −1.3% pp/y) and HHD sumscore (mean decline −2.6% pp/y). Although we found significant changes in muscle strength and some patients became wheelchair or ventilator dependent during follow-up, the QMFT did not indicate a deterioration in limb-girdle muscle function. There may be two main reasons for this. First, the decline in muscle strength may have been too small to cause changes in functional daily activities within the observed time-span. Second, although the QMFT showed a good discriminative ability and good responsiveness to change after start of enzyme replacement therapy, it may not be sensitive enough to reflect minor changes in strength in functional changes during the natural course
Mechanical ventilation became necessary in four of the 67 hitherto un-ventilated patients, eight patients needed to increase their number of hours of ventilation, and one patient died due to respiratory complications. Despite this indication that pulmonary function clearly worsened during the time-span of the study, our findings regarding the yearly decline seem somewhat lower than those of other studies.
[13, 27] This may have been due to our method of patient selection: in the present study participation was open to all adult patients with a confirmed diagnosis of Pompe disease, including those with very limited pulmonary function who were invasively ventilated 24 hours a day. Although this reflects the spectrum of disease encountered in daily practice, one would expect further deterioration of pulmonary function in these patients to be minimal, thereby partly obscuring decline in the total group. Secondly, when enzyme replacement therapy became commercially available, we decided first to treat the most severely affected patients and patients with a rapid decline in pulmonary function and muscle strength, while patients with a slow disease course were started on ERT at a later stage. As a result, the length of prospective follow-up for the most severely affected patients was somewhat shorter (1.1 years on average) than for the least affected patients (1.7 years on average, the longest follow-up being 4.2 years). Another factor that could have influenced the estimated rate of decline is the fact that data on seven patients who participated in the placebo arm of the randomized controlled trial on the safety and efficacy of alglucosidase alfa in late-onset Pompe disease were included in the present analyses. However, a second analysis, excluding these patients to overcome a possible placebo effect, led to similar estimates of the rate at which muscle weakness and pulmonary dysfunction progress (not shown).
It should be noted that all patients except one had the c.-32-13T>G (IVS1-13T>G) mutation in combination with a null allele. Although this is the most common genotype in adult Pompe patients – present in 68-93% of patients
[27, 40, 41] – the estimated rate of disease progression may not apply to patients with different genotypes.
Predictors for disease outcome and disease course variability
Longer disease duration (≥ 15 years) and pulmonary dysfunction (FVC <80%) were shown to be associated with a faster decline in muscle strength. Our results thus support those of the only other prospective study in adult Pompe patients, which found baseline status and duration of illness to be the most important predictors of disease severity and disease progress
A subset of patients with shorter average disease duration and better baseline status did not deteriorate during follow-up, indicating that there might be a stable phase of several years before a gradual decline inevitably occurs. This raises an interesting dilemma regarding the best time to start ERT.
 On the one hand, in patients who are only mildly affected and whose condition is stable, one might advocate that this – costly – lifelong treatment be postponed. On the other hand, studies measuring the effect of ERT show a trend toward better outcome in patients who were in a relatively good condition at the start of treatment.
[11, 13, 14] On the basis of our results, we suggest to start ERT in all patients with pulmonary dysfunction and in patients with progressive muscle weakness, whereas in patients with minimal weakness, or in patients with solely elevated laboratory parameters treatment may be postponed, provided that they are monitored regularly. At our center, all patients undergo evaluation of muscle strength, pulmonary function, cardiac function, and hearing at referral, and evaluation of progression of muscle weakness and pulmonary dysfunction every three months thereafter.