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.
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.
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.
At last assessment, the principal findings in the long-term survivors were the following:
The investigators derived several conclusions with implications for patient care from their findings.
The main ones are:
"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 ClinicalTrials.gov.
You also can send email to Help@pomperegistry.com, or call (617) 591-5500.
For more, see:
About Clinical Trials
A clinical trial is a test, in humans, of an experimental treatment. Although it's possible that benefit may be derived from participating in a clinical trial, it's also possible that no benefit, or even harm, may occur.
MDA has no ability to influence who is chosen to participate in a clinical trial.
To learn more, see Learn about Clinical Studies and Being a Co-Adventurer, which is about neuromuscular disease clinical trials. To see a continuously updated database of clinical trials, go to ClinicalTrials.gov.