Pompe disease (Type II GSD) is an autosomal recessive genetic disease that is caused by a lack of function of the enzyme acid alpha-1,4-glucosidase [also called acid maltase]. Type II Glycogen Storage Disease also belongs to a group of metabolic diseases called lysosomal storage disorders (LSDs). Type II GSD is part of both groups because the acid maltase enzyme works in a compartment of the cells in our body, called the lysosomes.
Just as the body is divided into organs, each with its own specific function, the cells themselves are divided into compartments called organelles. There are a number of different organelles in cells. When discussing Pompe disease, our interest is in an organelle called the lysosome. In different parts of the body, lysosomes are found in varying amounts in varying sizes. Lysosomes always consist of a central space filled with material that is completely enclosed by a membrane.
Lysosomes act as tiny garbage collectors in the cell. They keep cells working well by collecting anything that there is too much of in the cells. The substances they collect are then recycled into smaller parts and released into the cell again to be reused or disposed out of the cell. In Type II GSD disease the problem is in the breaking down of complex sugars (glycogen) that is in the lysosomes, into simple, easy to digest sugar (glucose) due to the defect in the enzyme called acid alpha glucosidase (GAA).
Without the proper function of this enzyme, the glycogen that enters into the lysosomes is not broken down, but continuously builds up and disrupts the normal functions of the lysosome. This means that in Pompe disease (Type II GSD disease), where there is no enzyme to break down the glycogen in the lysosomes, that the lysosomes in the heart (also known as cardiac muscle) and other muscles quickly accumulate large deposits of glycogen. Over time these large deposits of glycogen cause the lysosomes to grow larger and larger and eventually breakdown, thus disrupting the function of the cell and organs that the cells make up, in this case the heart and muscles.
GSD Type II is often divided into subtypes based on the age at which the disease first occurs, the severity of the disease and the rate at which the disease progresses. The amount of acid alpha glucosidase that remains active in individuals with Type II GSD plays a part in determining which type of Type II GSD an individual may have. In general, the more enzyme that is present in individual’s muscles, the later the onset of the disease, however there are exceptions.
It is broadly classified into infantile and late onset forms.
Infantile-onset form: With this form, infants usually present during early infancy (4-8 months of age) with weakness and floppiness, are unable to hold up their heads and cannot do other motor tasks common for their age, such as rolling over. The muscles in the arms and legs look typical, but are very weak. Breathing muscles are also weak. The heart muscle thickens (cardiomyopathy) and progressively fails in its blood pumping function. Without treatment, infants with Type II GSD usually die before 12 months of age due to heart failure and respiratory weakness.
Late/later onset forms (this includes juvenile and adult): With these forms, the disease has a later onset, usually at an age greater than one or two years of age. It progresses more slowly than the infantile form. A decrease in muscle strength is one of the first symptoms observed. Muscles slowly become weaker, especially the large muscles of the legs and trunk, and later the arms. Due to muscle weakness, walking/climbing stairs becomes difficult. The involvement of the muscle weakness progresses slowly over the years. Some adults with Type II GSD use a wheelchair or other assistance with mobility
Late onset Type II GSD also involves the muscles required for breathing (diaphragm and other muscles that assist with respiration). Over a period of time breathing becomes difficult. Some patients have presented with pulmonary (lung) insufficiency due to respiratory muscle weakness. An early finding is difficulty with nighttime breathing, and this can be an early clue. Difficulty breathing can be evaluated by an overnight sleep study. It may become necessary to use a Bi-Pap or ventilator machine to assist in breathing. Respiratory failure is the most common cause of death in individuals with adult Type II GSD. Heart muscle involvement does not appear to be a significant feature in late onset Type II GSD, but is seen in some individuals (heart rhythm disturbances and heart muscle thickness)
Genetics: Type II GSD is a genetic disorder. This means it is caused by a change in a part of an individual’s genetic information. Genetic information is stored on genes. Genes serve as the instruction manual for our bodies. They tell the body how to grow and function. They also determine physical features, such as hair color and eye color. A person has around a 30,000 genes in every cell of their body. Two sets of every gene are inherited, one set from the mother and one set from the father.
If there is a change in the genetic information contained on one of these genes, the body is unable to read the instructions. Therefore, it may cause a difference in the way the body functions. This is similar to having a page missing out of an instruction manual for putting an appliance together. Without that page, one would be unable to properly assemble the appliance and it would not be able to work. The gene responsible for making acid maltase is called the GAA gene. If one copy of the GAA gene is altered but the second copy is not, then the body can follow the instructions on the second copy in order to produce enough acid maltase enzyme. This is like having a second instruction manual to refer to. When both copies of an individual’s GAA gene are altered, the body is unable to read any instructions on how to make the proper amount of GAA/acid maltase enzyme. As a result, the individual has Type II GSD.
Diagnosis and testing: Type II GSD can be diagnosed by determining the activity of the enzyme acid alpha glucosidase. This deficiency can be shown with a specific enzyme testing that can be performed on blood samples, muscle biopsy or cultured cells from a skin biopsy. This type of testing is very specific and available at only a few specialized laboratories in the USA. Genetic testing for mutation finding and gene sequencing for Type II GSD is also available clinically from a limited number of laboratories in the USA. For many families, genetic testing is most helpful in providing additional information for the person with Type II GSD and other family members after the diagnosis is made and confirmed using enzyme (acid alpha glucosidase) testing.
If someone with muscle weakness has a muscle biopsy examined at their local hospital by pathology, testing called histopathology will show a great increase of glycogen of normal structure, and microscopic studies will show increased glycogen enclosed within the lysosomes. This type of testing, while helpful in determining that Type II GSD is a possible diagnosis, is not diagnostic for Type II GSD. In some people with Type II GSD, depending on where the piece of muscle was obtained, the muscle histopathy in the piece of muscle from the the muscle biopsy can be normal. If Type II GSD is suspected, then diagnostic testing is needed. These diagnostic tests can either test the function of specific enzyme acid alpha glucosidase or genetic testing looking for changes in the GAA gene can be performed.
Treatment: There is currently treatment available for individuals with Type II GSD. This treatment is called enzyme replacement therapy (ERT). The idea behind enzyme replacement therapy aims to replace the defective acid alpha glucosidase enzyme that people with Pompe disease either cannot make at all or cannot make enough of. It is a synthetic (recombinant, genetically-engineered), form of acid alpha glucosidase. ERT is given to patients as an intravenous (IV) infusion (an injection given over time directly into a vein). ERT for Type II GSD in the form of a product called Myozyme®. Myozyme® is manufactured and distributed by a company called Genzyme. If you have questions about enrolling in clinical trials or other therapy programs for Pompe disease, contact the Medical Information Department at Genzyme 800-745-4447 in the United States or 617-768-9000 from anywhere in the world.
Note: Since there is multisystem involvement and clinical variability, a team approach to medical care is optimal. Individuals with Pompe disease report the best success when they work closely with a coordinating physician, either primary care or specialist, familiar with the likely disease manifestations. Many specific issues related to Type II GSD should be addressed by a physician familiar with the needs of individuals with Type II GSD. For example, if an adult with Type II GSD uses a ventilator for breathing assistance, should be regularly evaluated and treated by a pulmonologist (breathing doctor). The best patient response or outcome is often achieved when the entire care team has an understanding of the unique and complex medical needs specific to individuals with Pompe disease.
Frequently involved specialties include:
•cardiology (infantile onset),
•speech / language pathology
Acid Maltase Deficiency Association: www.amda-pompe.org
Muscular Dystrophy Association [MDA] Resources: www.mdausa.org
MDA information on AMD
Metabolic Diseases of Muscle
”Living With Metabolic Myopathies”