Sizing Up Early Enzyme Replacement for Pompe Disease

A study of 11 long-term survivors of infantile-onset Pompe disease shows enzyme treatment can provide significant benefits, but deficits remain

Among long-term survivors of infantile-onset Pompe disease who started treatment as babies, growth followed typical curves, but residual muscle weakness, hearing impairment and risk for cardiac rhythm abnormalities persisted.
Article Highlights:
  • Researchers at Duke University and elsewhere have studied 11 children who are long-term survivors of infantile-onset Pompe disease.
  • Respiratory function, heart size, linear growth and cognitive development were normal in the survivors.
  • Several surviving children had abnormal heart rhythms, residual muscle weakness, reduced bone density, excessively nasal speech, hearing impairment or swallowing difficulties.
  • Early treatment with enzyme replacement therapy and the presence of some natural GAA enzyme production are correlated with a better prognosis in infantile-onset Pompe disease.
by Margaret Wahl on October 4, 2012 - 5:00am

A study of 11 children with infantile-onset Pompe disease (acid maltase deficiency) who started enzyme replacement therapy by the time they were 6 months old has shown the treatment can markedly improve the course of the disease, but that residual deficits persist.

Myozyme replaces missing enzyme, has improved survival

Not long ago, the outlook for children with infantile-onset Pompe disease was bleak. The disorder, which stems from a deficiency of the acid maltase enzyme, results in a buildup of the carbohydrate glycogen in the heart and skeletal muscles, including those involved in breathing.

The affected muscles weaken, causing cardiac and respiratory failure; and babies who did not receive treatment generally lived only about two years. (When the disease begins later in life, it is generally less severe.)

Since 2006, the intravenous drug Myozyme, an enzyme replacement therapy, has been widely available for Pompe disease. (The drug was tested in clinical trials for several years before that.) The biopharmaceutical company Genzyme developed Myozyme, with the help of basic science research data and supplemental financial support from MDA. (A similar drug, Lumizyme, also developed by Genzyme, became available in 2010 and is specifically for late-onset Pompe disease in the U.S.)

Myozyme and Lumizyme replace the missing or deficient acid maltase enzyme, also known as acid-alpha glucosidase, or GAA. These drugs have saved the lives of many children with infantile-onset Pompe disease, and improved the lives of children and adults with later-onset forms of the disorder. However, their benefits vary among individuals, a phenomenon not entirely understood.

One factor in the effectiveness of these enzyme replacement therapies appears to be the stage of the disease when the therapy is started, with individuals treated early having a better outcome.

Another factor is the extent to which the body's immune system tolerates the new GAA enzyme. That in turn seems to depend partly on how much GAA enzyme the person is making without treatment. People who make very little or no GAA enzyme of their own are more likely to develop antibodies (proteins generated by the immune system) against Myozyme or Lumizyme, lessening the effectiveness of these therapies.

Researchers studied 11 long-term survivors

Sean Prater at Duke University Medical Center in Durham, N.C.,  with colleagues there and at other U.S. institutions, have followed the course of infantile-onset Pompe disease in 11 children, publishing their findings in the September 2012 issue of Genetics in Medicine. Priya Kishnani, a medical geneticist and professor of pediatrics at Duke, was the senior investigator on the study.

The investigators looked at cardiac, respiratory and musculoskeletal measurements; gross motor function and walking ability; linear growth, speech, hearing, swallowing, gastrointestinal function and nutritional status; and school performance. They also looked at laboratory values reflecting disease activity.

They reviewed the medical records of children with infantile-onset Pompe disease, selecting those who developed symptoms by the age of 6 months; had GAA enzyme activity that was less than 1 percent of normal; had evidence of cardiomyopathy (cardiac muscle abnormality); were not receiving ventilatory support prior to starting enzyme replacement therapy; had started enzyme replacement therapy by 6 months; and had survived to at least 5 years of age.

Eleven children who were 5 to 12 years old — dubbed "long-term survivors" of infantile-onset Pompe disease — met these criteria and were included in the study. All the long-term survivors were found to be producing some (though a very small amount) of the self-generated GAA enzyme.

An additional six children with infantile-onset Pompe disease who received early enzyme replacement therapy were not included because they did not survive to age 5. None of these six was making any GAA enzyme. These children produced treatment-blocking antibodies to the enzyme replacement therapy, a likely cause for the disease progression and early death despite the enzyme therapy.

Early enzyme treatment beneficial, but not perfect

At last assessment, the principal findings in the long-term survivors were the following:

  • None of the 11 required invasive or noninvasive ventilatory support or supplemental oxygen.
  • Heart enlargement, which had been seen in all 11 long-term survivors before treatment, had resolved in everyone about five months after starting enzyme replacement therapy.
  • Five children had developed abnormal heart rhythms either before or during enzyme therapy, and three had required special treatment.
  • Seven of the 11 children were walking without assistive devices, and four were using walkers on either a full-time or part-time basis.
  • Generalized muscle weakness was present in 10 of the 11 children.
  • Six of the 11 had reduced bone density in the lumbar spine.
  • All 11 had followed typical curves for height and weight; median height was at the 64th percentile, and median weight was at the 54th percentile.
  • Ten of 11 had excessively nasal speech.
  • Nine of 11 had some degree of hearing impairment; seven were using hearing aids.
  • Seven of the 11 children were taking all their nutrition by mouth; four were on a combination of oral and gastrostomy tube nutrition.
  • Five children had swallowing difficulties
  • Three had gastroesophageal reflux.
  • All long-term survivors appeared to be functioning at their appropriate grade levels in school.
  • In 10 children for whom data were available, all had either no or low levels of antibodies to the GAA enzyme. (All 11 were producing small amounts of GAA enzyme, which may have helped "tolerize" them to the therapy.)

Results suggest need for regular ECGs, other exams

The investigators derived several conclusions with implications for patient care from their findings.

The main ones are:

  • Enzyme replacement therapy does not seem to be as effective against the development of abnormal heart rhythms (arrhythmias) as it is against other aspects of Pompe-related heart disease, suggesting a need for regular electrocardiograms (ECGs) and other cardiac follow-up in this disorder.
  • Residual muscle weakness is common; when it results in an imbalance of forces across the joints of a growing child, it may result in secondary orthopedic impairments, suggesting vigilance in assessment and management in this area.
  • Speech-related dysfunction, once it appears in Pompe disease, can persist even when enzyme replacement therapy is continued and even when targeted interventions such as speech therapy are utilized.
  • Swallowing difficulties and their associated risk of inhaling food or liquids into the respiratory tract (aspiration) are prevalent despite enzyme treatment and need to be watched.
  • There was no evidence of major cognitive impairment in the long-term, treated survivors of infantile-onset Pompe disease; detailed assessments and imaging studies might show more subtle abnormalities and could shed light on the effects of treatment on the brain.
  • None of the long-term survivors formed high levels of antibodies against the replacement enzyme, supporting the hypothesis that high antibody levels negatively affect treatment response and suggesting that antibody levels should be monitored over time.
  • Several factors — environmental, genetic and immunologic — appear to determine how a child with Pompe disease will respond to enzyme replacement therapy; the presence of some endogenous GAA enzyme production appears to correlate with a better response.

Pompe Disease Registry collecting more data

"The number and percentage of patients with IPD [infantile-onset Pompe disease] who are predicted to be long-term survivors is expected to increase as ERT [enzyme replacement therapy] continues to make an impact and as further advancements are made in patient management approaches and drug development," the investigators write.

"From our study data," they say, "it is clear that the constellation of clinical findings for long-term survivors with IPD appears to be in many respects distinct from those associated with late-onset Pompe disease. It will be important to continue to follow these and other long-term survivors with IPD to refine our understanding of factors associated with long-term survival and improved clinical outcomes."

The researchers note that their study is limited by its small size and other aspects of its design.

They say the Pompe Disease Registry, a database of medical information on people with Pompe disease, will be helpful in collecting more data.

Enrolling in the registry requires a physician's involvement and a patient's or parent's consent. For information, see Pompe Disease Registry, or enter NCT00231400 in the search box at

You also can send email to, or call (617) 591-5500.

More information

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