Overview of Pompe Disease

In 1931, 30-year-old pathologist Johannes C. Pompe presented findings of an infant patient who died at 7 months of age and had a very enlarged heart from an unknown cause.

Examination under a microscope showed that her muscles did not look normal and instead showed “stacks” of glycogen, a sugar-like substance. A few years and patients later, it was determined that this illness was due to a missing enzyme, and the condition was designated Pompe disease.

An Inherited, Progressive Disorder

Since then, much has been learned about the disease that Dr. Pompe first described. Pompe disease is a rare, inherited, genetic disorder that results in muscle weakness that is progressive, or gets worse over time, and in severe cases, can cause death.

Pompe disease is a genetic disease, meaning that people with Pompe disease inherit it as it is “passed down” from their parents. Patients with Pompe disease inherit a gene with a change, or mutation, from each of their parents.

If a person has 1 copy of the altered gene (also called a gene variant), they will not develop the disease; they are considered a “carrier.” The disease is only apparent when a person has 2 copies of the gene variant. This is referred to as autosomal recessive inheritance (Fig. 1). In Figure 1, both parents are carriers, so there is a 25% chance with each child born, that that child could inherit both variant genes and have the disease. See Pompe Disease and Family Genetics for more information.

A diagram showing autosomal recessive inheritance. Silhouettes of parents and a pair of their chromosomes illustrate that they both have a copy of the variant GAA gene. Silhouettes of four children and a pair of their chromosomes illustrate the possibilities of being an affected child, an unaffected child, or an unaffected child who is a carrier.

Pompe disease can be very variable with respect to the age at which it occurs, the symptoms a person experiences, and the severity of symptoms. Pompe disease can occur in people of all ages, from infants to adults and the elderly, but with different severity of symptoms.

Regardless of the severity of the symptoms or when they first appear, the cause of Pompe disease is always the same: the enzyme acid alpha-glucosidase (pronounced “AL-fa glue-CO-sih-days” and also referred to as GAA) is either not functioning properly, present in low quantities, or missing altogether. Generally the less GAA enzyme a person has, the more severe symptoms will be. This enzyme deficiency causes a form of sugar called glycogen to accumulate, which in turn causes muscles and organs to malfunction and eventually stop working. The progressive nature of this disease means that it will continue to worsen over time. However, the speed at which the disease progresses will vary from patient to patient and also depends on the disease subtype.

You may also hear Pompe disease referred to by different names:

  • Acid maltase deficiency (AMD)
  • Glycogen storage disease (GSD) type II
  • Glycogenosis type II
  • Acid alpha-glucosidase deficiency
  • Lysosomal alpha-glucosidase deficiency

How Does Pompe Disease Affect the Muscles?

The GAA enzyme is found inside the cells in a compartment called the lysosome. The GAA gene is responsible for making this enzyme. When a child inherits a pair of altered genes from 2 parents who are carriers, as described above, the result is decreased or absent levels of the GAA enzyme.

Under normal circumstances, this enzyme works in the lysosome to break down the complex sugar glycogen into glucose so the cell can use it for energy. Without the GAA enzyme, glycogen accumulates in the lysosome and affects the functioning of the cells and tissues. The tissues most severely affected are skeletal muscle (muscles used for voluntary movement, such as walking or lifting) and other types of muscles, including the heart and those used for semi-involuntary actions like breathing. Over time, this buildup of glycogen causes organs to function improperly and eventually fail, resulting in muscle weakness, breathing problems, and, in some cases, reduced life expectancy.

In the infantile-onset form of the disease, glycogen accumulation is most severe in the heart and skeletal muscles. But in the late-onset form, mostly the skeletal muscles are affected, which accounts for differences in disease symptoms and severity.

Pompe Disease by the Numbers

The incidence of a disease refers to the rate, or number, of new cases diagnosed in a given time period. The prevalence of a disease refers to the overall number of people affected with a particular disease. Although numbers vary, it is estimated that in the United States, Pompe disease occurs at around 1 in every 40,000 live births. However, as with any rare disease, it is difficult to know exactly how many people are actually affected. Assuming these incidence numbers are correct, it is estimated that the prevalence of Pompe disease may be 5,000 to 10,000 people worldwide. It occurs equally in males and females but varies depending on race and geographic location.

Introduction to Infantile-onset Pompe Disease and Late-onset Pompe Disease

Pompe disease can look like many different diseases because its symptoms vary from person to person. Two different subtypes or forms of the disease have been described: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). Although the age when symptoms first appear typically defines the subset of Pompe disease, a proper diagnosis relies on the clinical presentation as well. Below is a description of the 2 subtypes.

There are 2 types of IOPD: the “classic” form and an alternate form called the “nonclassic” or “atypical” form. The classic form of IOPD describes a relentless, severe form of the disease in which infants develop symptoms and are usually diagnosed within days to months of birth. Symptoms progress very quickly, and death almost always occurs by 1 year of age, mainly by heart or breathing failure. Because the course of this form of the disease is so rapid, prompt diagnosis is very important. This form is characterized by the following signs and symptoms

  • Lack of muscle tone (“floppy” appearance)
  • Muscle weakness (Fig. 2)
  • Enlarged heart on x-ray and heart muscle malfunction
  • Breathing difficulties
  • Feeding difficulties

A healthcare provider holding an infant with classic IOPD to demonstrate floppiness and poor muscle tone.

Figure 2. “Classic” IOPD. An infant with “classic” IOPD demonstrating “floppiness” and poor muscle tone.

The other type of IOPD is referred to as “nonclassic” or “atypical” IOPD because it is also diagnosed in infants, like the “classic” form, but the symptoms are not as severe. Symptoms first become obvious during infancy but may be delayed by a few months compared to the “classic” form. One of the most important differences is that these patients develop an enlarged heart muscle, but this development is delayed and not nearly as severe as in patients with the “classic” form of IOPD.

People with this form of Pompe disease generally live longer than patients with the “classic” form and their life expectancies may be extended with appropriate medical care. Serious medical problems leading to reduced life expectancy in these patients are usually from breathing disorders, not heart failure.

Patients with LOPD can start to have noticeable symptoms anywhere from >1 year of life to 20 to 60 years of age. This form is characterized by a slow progression of symptoms that are milder than those seen in the infantile form. These patients typically do not have enlargement of the heart as seen in IOPD forms of the disease. Symptoms include:

  • Muscle weakness/stiffness resulting in atrophy (muscle shrinking), weakness, and difficulties moving
  • Back pain
  • Shortness of breath, sleep apnea (multiple instances of interrupted breathing during sleep), daytime tiredness

Progression of Pompe Disease

The progression of symptoms in LOPD is slow relative to IOPD, with a gradual muscle weakening that results in walking and breathing problems. Patients may eventually need assistance walking or assistive devices to help with breathing (continuous positive airway pressure [CPAP] machine or ventilation). The disease course varies from person to person in LOPD; symptoms could be mild and progress slowly, or they could progress rapidly. Predicting the course of this disease is difficult, and monitoring symptoms as they arise is important for disease management.

Pompe – Mechanism of Disease