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Pompe disease is a rare, multisystemic, autosomal recessive disease also known as glycogen storage disease type II. It is caused by the lack or deficiency of lysosomal acid-alpha-glucosidase (GAA), which leads to the accumulation of glycogen within lysosomes that manifests as a multisystem disorder. There was no specific treatment for Pompe disease until the first enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA) was approved in the European Union and the United States in 2006.1

Two phenotypes of the disease are widely accepted: severe infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The first one appears in infancy and, if untreated, has a natural history of fast progression that leads to death from heart failure in the first year of life. The latter one can appear as late as adulthood with proximal muscle weakness and respiratory decline, usually without heart failure.2,3 Respiratory failure is the main cause of death in patients with LOPD.3

Although it is a progressive disease, studies showed significant improvement in the outcomes of patients with IOPD and LOPD treated with disease-modifying treatments using ERT.4,5 The therapy was shown to be particularly beneficial for patients with IOPD, who lived substantially longer as a result of the drug’s remarkable efficacy. On the other hand, long-term studies evaluating the efficacy of ERT in patients with LOPD found there was an initial improvement in respiratory function followed by regression, with a variable treatment response at an individual level.6-10

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Improved Walking Distances and Muscle Strength

In a recent systematic review and meta-analysis of the literature, Sarah and Giovanna et al intended to give an update on the existing data on the clinical effectiveness of ERT in patients with LOPD. The authors targeted randomized controlled trials (RCTs), prospective observational studies, and retrospective studies with more than 10 patients that evaluated rhGAA effects in patients with LOPD to be included in their study.11

The meta-analysis included clinical data from 589 individuals with LOPD from a total of 16 studies published between 2010 and 2020 with follow-up times from 6 months to 7 years. The authors particularly focused on motor performance, respiratory function, and muscular strength relative to baseline values by extracting data from included studies on six-minute walk test (6-MWT), forced vital capacity (FVC), medical research council (MRC), quantitative muscle testing (QMT), and quick motor function test (QMFT).11 The authors explain the rationale for this approach, stating that 6-MWT, FVC, and muscular strength were the initial functional assessments suggested by the Swiss Guidelines of Pompe Disease, and these were the same outcomes recommended by the European Pompe Consortium.12,13

Read more about Pompe disease therapies

Looking at the results of the conducted study, we can observe that patients receiving rhGAA improved their walking distance significantly (average 32.22 m (95% CI, 14.98–49.47; P =.0003) based on the results concerning 6-MWT reported in 14 studies including 419 patients (of those, 407 were treated with rhGAA) with LOPD. Muscle strength showed a nonsignificant improvement (0.07 points (95% CI, 0.05–0.19; P =0.24) according to the results based on 575 measurements of muscle strength at baselines and 549 measurements after ERT assessed with MRC, QMT, or QMFT from 10 studies including 413 patients with LOPD (of those, 388 were treated with rhGAA).

Results concerning FVC from 16 studies including 563 patients (including 555 who were treated with rhGAA) showed no significant changes in FVC (- 0.01% (95% CI, 2.48–2.45; P =0.99) over the observation period, compared to the values at baseline. The meta-analysis also showed that the FVC of patients treated with ERT did not improve beyond 20.75 months.11

These results were consistent with the findings of previous systematic reviews. Nevertheless, as the authors noted, this study is one of the few systematic reviews with a meta-analytic approach that explicitly refers to patients with LOPD, and  — unlike in the previous reviews — muscle strength was included as an outcome of interest.11

Variations in Duration of Treatment Effects

The majority of LOPD patients benefit from ERT, however, some individuals continue to deteriorate despite therapy. In general, LOPD patients’ responses to treatment are highly variable, and the causes for this heterogeneity as well as predictors of the therapeutic response are unknown.

The authors discuss how phenotypic and genotypic factors associated with LOPD, a diagnostic delay that may postpone an earlier start of ERT, and the development of antibodies against ERT may all play a role in treatment response because the results of the systematic review and meta-analysis are in line with previous findings from other studies.11

Read more about guidelines for treating Pompe disease

At this point, it might also be beneficial to emphasize the probable role of exercise training in combination with a high-protein diet in LOPD patients on long-term ERT. Slonim et al examined the effects of a high-protein diet combined with exercise training in LOPD prior to the introduction of ERT and found a reduction in the disease progression rate.14 Recently, in a crossover study, it was shown that a high-protein diet combined with moderate-intensity aerobic exercise increased exercise tolerance, muscle enzymes, pulmonary function, and quality of life in LOPD patients on long-term ERT.15

Therefore, complementary strategies such as dietary and exercise protocols concomitant to ERT might improve patient outcomes, based on current knowledge on the efficacy of long-term ERT in LOPD and emerging data regarding the strategies. However, further studies are required to confirm the effectiveness of supportive strategies.

New Therapeutic Approaches for Pompe Disease

As with most of the other rare diseases, research progress on Pompe disease is slow due to the low number of patients. Nonetheless, several approaches to improve therapy effectiveness are being investigated, such as increased ERT dose and frequency, immunomodulation with ERT initiation, several next-generation ERTs that aim to improve muscle-specific uptake, ERT combined with a chaperone, as well as gene therapies.16 Advances in diagnostic technology and newborn screening will also contribute to improving outcomes of the treatment by reducing the time to diagnosis. We can expect developments in the near future that will address unmet needs, answer pending questions, and lead to improvements in diagnosis, treatment, and disease management in Pompe disease.


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  2. van den Hout HM, Hop W, van Diggelen OP, et al. The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the literature. Pediatrics. 2003;112(2):332-340. doi:10.1542/peds.112.2.332
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  8. Semplicini C, De Antonio M, Taouagh N, et al. Long-term benefit of enzyme replacement therapy with alglucosidase alfa in adults with Pompe disease: prospective analysis from the French Pompe Registry. J Inherit Metab Dis. 2020;43(6):1219-1231. doi:10.1002/jimd.12272
  9. Stockton DW, Kishnani P, van der Ploeg A, et al. Respiratory function during enzyme replacement therapy in late-onset Pompe disease: longitudinal course, prognostic factors, and the impact of time from diagnosis to treatment start. J Neurol. 2020;267(10):3038-3053. doi:10.1007/s00415-020-09936-8
  10. Gutschmidt K, Musumeci O, Díaz-Manera J, et al. STIG study: real-world data of long-term outcomes of adults with Pompe disease under enzyme replacement therapy with alglucosidase alfa. J Neurol. 2021;268(7):2482-2492. doi:10.1007/s00415-021-10409-9
  11. Sarah B, Giovanna B, Emanuela K, Nadi N, Josè V, Alberto P. Clinical efficacy of the enzyme replacement therapy in patients with late-onset Pompe disease: a systematic review and a meta-analysis. J Neurol. Published online April 13, 2021. doi:10.1007/s00415-021-10526-5
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  13. van der Ploeg AT, Kruijshaar ME, Toscano A, et al. European consensus for starting and stopping enzyme replacement therapy in adult patients with Pompe disease: a 10-year experience. Eur J Neurol. 2017;24(6):768-e31. doi:10.1111/ene.13285
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  16. Davison JE. Advances in diagnosis and management of Pompe disease. J Mother Child. 2020;24(2):3-8. doi:10.34763/jmotherandchild.20202402si.2001.000002