Rare Disease Report

Exercise and Pompe Disease

AUGUST 12, 2015
RDR Staff
New research recently published online in the Orphanet Journal of Rare Diseases suggests that regular exercise routine can help patients with Pompe disease who are also taking enzyme replacement therapy(ERT).1

Pompe disease is a rare, oft-fatal form of muscular dystrophy.2 The inherited lysosomal storage disorder, estimated to occur in roughly 1 out of every 40,000 live births, is the collective consequence of approximately 300 genetic mutations in a gene that manufactures acid alpha-glucosidase (GAA), an enzyme that metabolizes glycogen.3 Normally, GAA processing of glycogen (a stored form of sugar) takes place in the lysosomes, cytoplasmic organelles that function as intracellular `recycling centers,’ eliminating debris and breaking down multiple substances into manageable components that are subsequently utilized or disposed of via other cellular processes.3 As a result of its interaction with GAA, glycogen is converted into glucose, utilized to provide muscle-fueling energy.3

Pompe disease is characterized by the absence or scarcity of the GAA enzyme.1,3 When this crucial protein is lacking, lysosomal glycogen accumulates throughout the body, leading, in severe cases, to a slew of serious debilitations and, in many cases, premature death.1,3 Symptomology is wide ranging, affecting multiple systems; however, the disease exacts a disproportionately debilitating toll on skeletal muscles (the hip, abdominal and paraspinal muscle groups are affected most acutely), the heart and the respiratory system.1,3

Both disease severity and age-of-onset are extremely variable and depend on degree of GAA deficiency. The early-onset manifestation, in which an absolute or near absolute GAA deficiency exists, tends to be more severe. Pompe-stricken infants can experience marked enlargement of the heart and tongue, feeding problems, poor weight gain, muscle weakness, and respiratory distress complicated by lung infection. The majority will perish due to Pompe-linked cardiac or respiratory sequelae prior to their first birthday. Late-onset Pompe disease, a partial GAA deficiency, has an onset age which ranges from the roughly 10 to 60. It can also result in death (following several years of disease progression, during which worsening muscle weakness begins to impact respiration, culminating in eventual death owing to respiratory failure). In contrast to the cardiologic issues observed in early-onset, the heart generally remains uninvolved.3  

Enzyme replacement therapy (ERT) has been the gold standard of treatment since the first ERT combination therapy (alglucosidase alfa) attained US Food and Drug Administration (FDA) approval for an early-onset Pompe indication in 2006 (approval for an almost biologically identical form of alglucosidase alfa for late-onset Pompe followed in 2010).1-3 Although the therapy is not curative, benefits of the agent have been demonstrated to include increased skeletal muscle strength, walking distance, respiratory function and survival rates.1

Lifestyle Change Associated with Enhanced Muscular Health

Researchers affiliated with the Erasmus MC University Medical Centre, Rotterdam, The Netherlands, recruited 25 adults (ranging in age from 20 to 71) with relatively mild, ERT-treated (for a period of at least 52 weeks), late-onset Pompe disease to engage in 3 exercise sessions per week over a period of 12 weeks.1

Work-outs were supervised by physical therapists and consisted of repetitive sets of standardized activities designed to improve strength, resistance and core stability coupled with an aerobic component. Subjects maintained training diaries tracking a range of self-reported, fitness-related data (type/duration/intensity of exercise) and were telephoned weekly in order to assess progress and motivation. Every 2 weeks, measurements of plasma creatine kinase activity were performed to assess exercise-induced muscle damage.

Pompe Patient Training Routine1

Primary endpoints included before-and-after measures of safety, endurance and muscle strength. Secondary endpoints evaluated core stability, muscle function and body composition. Patient assessments were conducted at week 0, 12 and 24.

Citing evaluated data from 23 of the 25 enrolled subjects who completed it (2 dropped out due to lack of motivation), investigators linked the Pompe patient exercise program with increased endurance, lung capacity, strength and balance. No adverse events were reported. Highlights gleaned from key findings are summarized below. “Our study shows that a combination of aerobic, strength and core stability exercises is feasible, safe and beneficial to adults with Pompe disease,” wrote researchers.

Key Findings

 Increased maximum workload capacity
  • 110 W before to 122 W after training, [95% CI of the difference 6 .0 to 19.7])
Increased maximal oxygen uptake capacity
  • 69.4% and 75.9% of normal, [2.5 to 10.4])
Increased maximum walking distance
  • 6-minute walk test: 492 meters and 508 meters, [−4.4 to 27.7], P = .01)
Increased muscle strength
  • Hip flexors (156.4 N to 180.7 N [1.6 to 13.6)
  • Shoulder abductors (143.1 N to 150.7 N [13.2 to 35.2])
Increased muscle function
  • Reduced time required to climb 4 steps  (on average .3 seconds less, [−.54 to −.04], P = .02)
  • Reduced time required to rise from supine to a standing position (1 second less, [−2.0 to .01], P = .05).

Pompe Progress Not Limited to Latest News

Evidence that regular fitness training can improve Pompe disease patient health and augment ERT therapy represents 1 of several novel insights into the condition. In the realm of genomic-pharma research, several investigatory initiatives are currently underway. Bio-therapy candidate BMN 701 (GILT-tagged Recombinant Human GAA), for example, is currently engaged in a long-term Phase 3 trial, in eventual pursuit of a late-onset Pompe disease indication.4,5

According to manufacturer BioMarin Pharmaceutical Inc., San Rafael, California, BMN 701 has a different mechanism of action then alglucosidase alfa, employing an attached protein (IGF-2) which allows it to target delivery to the lysosome more accurately and attach more tightly to cellular surfaces than the naturally-occurring GAA enzyme.4 In early-stage research, BMN demonstrated both cell penetration and the ability to remove excess glycogen.4

"Research and treatment options for Pompe disease have come a long way," summarized Tiffany House, President, Acid Maltase Deficiency Association, San Antonio, Texas.4


  1. van den Berg LE, Favejee MM, Wens SC, et al. Safety and efficacy of exercise training in adults with Pompe disease: evaluation of endurance, muscle strength and core stability before and after a 12 week training program. Orphanet Journal of Rare Diseases 2015. http://www.ojrd.com/content/10/1/87 Published online July 19, 2015.
  2. Valeo T. Treatment for Adult-onset Pompe Disease Tried in First U.S. Patient. Dana Foundation Online News http://www.dana.org/News/Details.aspx?id=43099 Published September 10, 2010. Accessed online July 30, 2015.
  3. National Institute of Neurological Disease and Stroke (NINDS) website. NINDS Pompe Disease Information Page. http://www.ninds.nih.gov/disorders/pompe/pompe.htm Updated February 20, 2013. Accessed July 30, 2015.
  4. BioMarin Doses First Patient in Phase 3 INSPIRE Trial With BMN 701 for the Treatment of Pompe Disease [press release]. San Rafael, California. May 27, 2014. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=850509
  5. US National Institutes of Health Clinicaltrials.gov website. BMN 701 Phase 3 in rhGAA Exposed Subjects With Late Onset Pompe Disease. https://www.clinicaltrials.gov/ct2/show/NCT01924845?term=Pompe+disease+AND+Phase+3&no_unk=Y&rank=1 Updated March 23, 2015. Accessed July 30, 2015.
Image of children exercising courtesy of the National Cancer Institute.

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