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Understanding Pompe Disease
What Is Pompe Disease?
Pompe (POM-pay) disease, also known as glycogen storage disease type II or acid maltase deficiency, is a rare genetic disorder that results in profound muscle weakness. The disease is caused by mutations in the gene that instructs the body to make an enzyme called acid alpha-glucosidase (GAA). Normally, the body uses this enzyme to break down glycogen (stored sugar) into glucose (sugar). But in Pompe disease, GAA is absent or significantly reduced, causing excessive amounts of glycogen to accumulate in the body’s tissues, which results in major damage. The heart and skeletal muscles are most affected.
Pompe disease is an autosomal recessive condition—meaning that each parent of an affected individual must pass on a copy of the mutated gene. This is part of the reason that the disease is relatively rare, affecting 1 in 40,000 people.
Two forms of Pompe disease have been identified: a severe “infantile” form and a milder “late-onset” form. The infantile form of the disease usually occurs within the first months of life and progresses rapidly, with severe muscle weakness, heart failure, and often death before the age of 1 or 2. The late-onset form of the disease (also referred to as the juvenile/adult form) presents after infancy and progresses more slowly. Muscle weakness is the primary symptom, and the heart is typically spared. Life expectancy is usually shortened due to weakness of the respiratory (breathing) muscles in people with this form of the disease.
Pompe disease is diagnosed by screening for the common mutations in the GAA gene, by measuring the level of the GAA enzyme in a blood sample, or by a muscle biopsy. Once a diagnosis is obtained, consultation with a geneticist and screening of other family members is recommended.
The U.S. Food and Drug Administration has approved alglucosidase alfa (Myozyme)1 for use in patients with Pompe disease. A type of enzyme replacement therapy, Myozyme is a form of GAA—the enzyme that is absent or reduced in the disorder. The drug is usually administered via intravenous infusion every other week. Myozyme has been remarkably successful in reversing cardiac muscle damage and in enhancing life expectancy in those with the infantile form of the disease. The therapy, however, is less effective in skeletal muscle.
1 Brand names included in this booklet are provided as examples only, and their inclusion does not mean that these products are endorsed by the National Institutes of Health or any other Government agency. Also, if a particular brand name is not mentioned, this does not mean or imply that the product is unsatisfactory.
People with Pompe disease need highly specialized care from a variety of specialists, especially as the disease progresses.
For the past two decades, researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Dr. Paul Plotz, Chief of the NIAMS Arthritis and Rheumatism Branch, and a group of scientists in his lab led by Dr. Nina Raben, have made significant strides toward our understanding of Pompe disease. Although it was originally hoped that enzyme replacement therapy could cure Pompe disease, the NIAMS group discovered that skeletal muscle is resistant to the treatment. This finding was made in mouse models of the disease that were generated in the lab; these models are now used throughout the world by scientists involved in the research and development of Pompe therapies.
The group is focusing its current efforts on using the new information to improve treatment of the resistant muscle fibers. These studies are partially funded by a cooperative research and development agreement (CRADA) with Genzyme, the company that produces Myozyme.
The NIAMS group recently uncovered new clues related to the cellular defects in Pompe disease. They identified structures in many skeletal muscle cells in Pompe patients and mice that appeared to be large collections of cellular debris that should have been delivered to, and processed in, the lysosomes, the “recycling centers” of the cell. This debris would normally have been digested in the lysosomes into the building blocks that the cell uses to keep itself in shape—amino acids to build proteins, sugars like glucose to provide energy, and fatty acids to build membranes and to provide energy. They found that not only were the lysosomes filled with glycogen that could not be digested, but that other materials were building up outside and were unable to reach the recycling place. This buildup looked like the kind of material that is normally carried to the lysosomes by a remarkable system, called “autophagy”—which literally means “self-eating.” This system picks up worn out cell parts for delivery to the lysosomes for recycling. Dr. Raben recognized that this pick-up and recycling system does not function properly in Pompe skeletal muscle, and the stressed recycling centers appear to be overwhelmed. The NIAMS group is currently testing new strategies to intervene in Pompe disease by exploring ways to modulate the autophagic machinery.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. The NIAMS information clearinghouse is a public service sponsored by the NIAMS that provides health information and information sources. Additional information can be found on the NIAMS website at www.niams.nih.gov.
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Additional copies of this publication are available from:
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health
NIH Publication No. 10–7581