Introduction
Pompe disease (OMIM # 232300) is a progressive metabolic disorder that was first described by the Dutch pathologist J.C. Pompe in 1932 (Pompe
1932). It is caused by deficiency of the lysosomal enzyme acid α-glucosidase (
GAA). This deficiency results in intracellular glycogen accumulation, mainly in muscle cells, and gives rise to a broad clinical spectrum dominated by skeletal muscle weakness (Hirschhorn and Reusser
2001; van der Ploeg and Reuser
2008).
At the most severe end of the spectrum, classic-infantile patients present with hypertrophic cardiomyopathy and general muscle weakness. Without enzyme replacement therapy (ERT), these infants usually die within the first year of life (van den Hout et al
2003; Kishnani et al
2006). More slowly progressive forms of Pompe disease can manifest in children and adults, with onset ranging from early infancy until (late) adulthood. These presentations are characterized by limb-girdle and respiratory muscle weakness, resulting in ventilator and/or wheelchair dependency. The heart is rarely involved (Engel et al
1973; Laforet et al
2000; Slonim et al
2000; Van der Beek et al
2009; van der Beek et al
2011; Gungor and Reuser
2013). While there are similarities between children and adults with these non-classic presentations, there are also differences, especially in terms of disease severity. Our recent cross-sectional study of 31 untreated children with non-classic presentations showed that 25% needed a wheelchair during childhood, 48% had decreased pulmonary function, 25% needed respiratory support, and two died before reaching adulthood (van Capelle et al
2016).
In 2006, ERT with alglucosidase alfa was approved for patients with Pompe disease. ERT has been shown to reverse the hypertrophic cardiomyopathy and increase survival in classic-infantile patients (Van den Hout et al
2000; Kishnani et al
2007). In adult patients, positive effects were also demonstrated on endurance, muscle strength, pulmonary function, and survival (Bembi et al
2010; Strothotte et al
2010; van der Ploeg et al
2010; Angelini et al
2012; de Vries et al
2012; Regnery et al
2012; van der Ploeg et al
2012; Anderson et al
2014; Stepien et al
2016; Van Der Ploeg et al
2017). However, as not all of these patients respond equally well, it has been speculated that ERT should be started early to provide the best result (Strothotte et al
2010; van der Ploeg et al
2010; Angelini et al
2012; de Vries et al
2012).
Here, we present the long-term follow-up during ERT (median of 6.8 years) of 17 children with Pompe disease of various severity. The longest follow-up after start of ERT was 15 years.
Discussion
This study presents the follow-up of 17 patients with non-classic presentations of Pompe disease who had started ERT during childhood. After 7 years of treatment, there were group-level improvements in the QMFT and in the distance walked (6MWT), while the MRC and HHD seemed to remain stable. For a progressive disorder in which all these outcomes are anticipated to decline (Wokke et al
2008; van Capelle et al
2010; van der Ploeg et al
2010; van der Beek et al
2011; de Vries et al
2012; van der Beek et al
2012), these results demonstrate that ERT has a positive effect in children.
The improvement in the QMFT is extremely relevant to patients, since this test measures the ability to perform everyday movements that are particularly difficult for Pompe patients, such as squatting, raising the hands above the head, or doing a sit-up. For two reasons, we believe that our results are robust: we included a relatively large group of children who were followed over a long period, and the observed effects were sustained despite multiple testing correction. While patients’ individual response patterns support these results, they also indicate that not all patients benefit equally from treatment.
Generally, patients’ motor outcomes responded better compared to their pulmonary function. The poorer response with regard to lung function might be due to the involvement of the diaphragm (Pellegrini et al
2005; Prigent et al
2012; Gaeta et al
2013; Wens et al
2015; Mogalle et al
2016). This involvement is also illustrated by the fact that fewer patients were able to perform lung-function assessments in supine position. Our statistical analyses show that lung function declined significantly in sitting position, and tended to decline in supine position. These declines were similar in extent (4-5 pp. over 7 years). In untreated adult patients and children, FVC has been reported to decline between 1 pp. and 5.5 pp. per year (Wokke et al
2008; van Capelle et al
2010; van der Ploeg et al
2010; van der Beek et al
2011; de Vries et al
2012; van der Beek et al
2012). This is greater than the decline we observed over 7 years, suggesting that disease progression in terms of lung function slows down during ERT.
Our results also suggest that males responded more poorly with regard to lung function than females. However, this difference needs to be interpreted with caution, since there were fewer females than males, and since this difference could be demonstrated in sitting position only. Nevertheless, a similar trend in gender difference was reported in the multicenter randomized placebo-controlled study in 90 adult patients with Pompe disease (van der Ploeg et al
2010). It should be investigated whether such gender differences truly exist.
The individual response to treatment varied considerably between patients, and it would be very relevant to identify its causes. In general, treatment success is believed to be correlated with an early start of treatment, i.e., when patients are still mildly affected. We found that this paradigm does not hold for all patients: some patients with clearly reduced pulmonary and/or motor function improved or stabilized, while some whose initial clinical status was good deteriorated on ERT.
Other factors that could be involved in the response to ERT are the type of mutation in the GAA gene, genetic background factors such as the ACE polymorphisms (Ravaglia et al
2012; De Filippi et al
2014; Baek et al
2016), or antibodies against ERT with alglucosidase alfa. For five of our patients we have 3 years of data on antibody titers; in all five, these were low (van Capelle et al
2010). It was also shown in adult patients that the vast majority had low antibody titers, while a counteracting effect was demonstrated only in incidental cases (de Vries et al
2017). All in all, more research is needed to fully understand and predict which patients respond well to treatment and which do not. Patients responding less well to ERT might benefit from new or personalized treatment options.
Noteworthy, 14 of the 17 children (82%) in our study had the same common genotype, the c.-32-13 T > G GAA gene variant in combination with a null allele, as found in over 90% of the Caucasian adult Pompe patients. This highlights that the group of patients with the c.-32-13 T > G/‘null’ GAA genotype represent a broad clinical spectrum.
Some outcome measures could not be assessed in all wheelchair and/or ventilator dependent patients. The 6MWT can only be performed in patients who are able to walk, and the results may therefore not be generalizable to the most severely affected patients. This is also partly true for the QMFT and FVC.
Few studies have been published on the effects of ERT in children. Studies on late-onset patients occasionally include children: a review from 2013 identified 27 children amongst 368 patients in 21 papers (Toscano and Schoser
2013). However, most of these studies do not provide separate information on children. Supplemental Table
2 summarizes the results of eight publications that report on the outcomes of children treated with ERT (Winkel et al
2004; Rossi et al
2007; van Capelle et al
2008; Bembi et al
2010; van Capelle et al
2010; Ishigaki et al
2012; Deroma et al
2014; Porta et al
2015). The number of children included per study ranged from one to eight; follow-up ranged from 1.3 to 8 years (in most studies, follow-up was around 3–4 years). These studies suggest that patients’ motor function and muscle strength tend to improve, and their lung function is stable or possibly improves. The present study, which describes long-term findings, is partly in line with this. Upon analysis of the individual follow-up of five of our patients who had previously been described after 3 years of treatment, we found that, with longer follow-up (up to seven more years in the current study), two had started to decline, while the others had continued to improve or to stabilize (van Capelle et al
2010). These observations stress the continuing importance of regular long-term patient follow-up.