Types of Pompe disease

Last updated Oct. 15, 2024, by Marisa Wexler, MS
Fact-checked by José Lopes, PhD

Pompe disease is a rare, inherited, and progressive genetic condition characterized by muscle weakness. It is now generally classified into three types:

• classic infantile-onset Pompe
• nonclassic infantile-onset
• late-onset Pompe disease.

The three types of Pompe differ based on the age at which symptoms first become apparent (called the age of onset), as well as their severity.

The first descriptions of the disease in medical literature commonly used “late-onset” to describe people who developed symptoms as adults, while terms like “juvenile Pompe” were sometimes applied to patients whose symptoms appeared in later childhood.

But with the advent of enzyme replacement therapy (ERT) in the 2000s, and with increasing medical knowledge, the distinction of Pompe disease types is now mainly based on the presence or absence of cardiomyopathy, or disease of the heart muscle, in early life. Classic infantile-onset Pompe, which usually includes cardiomyopathy, is the most severe type of the disease.

What are the different types of Pompe disease?

Also known as glycogen storage disease type 2, Pompe is caused by mutations in the GAA gene, which provides instructions for making an enzyme called acid alpha-glucosidase. Each form of Pompe is partially associated with specific mutations in GAA.

In general, mutations that lead to a total loss of the enzyme’s function are associated with an earlier age of onset and more severe Pompe disease symptoms. By contrast, variants that produce an enzyme that partially works are linked to milder and later-onset disease.

The acid alpha-glucosidase enzyme breaks down the complex sugar molecule glycogen into a simple sugar, glucose, which cells can metabolize for energy. In Pompe disease, due to the mutations in GAA, the enzyme either doesn’t function correctly or is fully absent, so glycogen builds in tissues and causes damage — especially in muscles.

Because all cases are caused by GAA mutations, a Pompe diagnosis and disease treatment strategies are similar among the three types. The main difference among them concerns the timing and severity of symptoms, especially cardiomyopathy.

Classic infantile-onset Pompe disease

Symptoms of classic infantile-onset Pompe disease become apparent within the first few months of life, typically around age 4 months. Patients with this disease form usually have less than 1% of normal GAA enzyme activity.

Early symptoms often include poor feeding due to muscle weakness in the face and tongue, which leads to slow growth (failure to thrive). Other common early complications include delayed motor development, difficulty breathing, respiratory infections, and hearing loss. Cardiomyopathy is common in this type of Pompe disease and usually becomes apparent in the first months of life.

Without treatment, babies with classic infantile-onset Pompe disease usually do not survive past age 2 due to heart and/or respiratory failure. ERT has been improving survival and other outcomes by reducing the accumulation of glycogen and curbing the progression of muscle damage.

Nonclassic infantile-onset Pompe disease

Nonclassic infantile-onset Pompe disease tends to begin within the first year of life, but usually later than in the classic form in which symptoms emerge within a few months of birth.

Symptoms of nonclassic infantile-onset Pompe disease generally are less severe than in the classic form and typically include progressive muscle weakness and delayed development of motor skills, such as rolling over and sitting up in infancy and early childhood. Breathing problems often develop as the disease progresses.

Some children with this form of Pompe disease will experience heart problems such as an enlarged heart (cardiomegaly), but the progression of heart problems usually is slower than in the classic form, and cardiomyopathy generally does not appear in the first year of life.

While nonclassic infantile-onset Pompe disease is often considered to be its own distinct subtype, some classification systems consider only two types, infantile-onset and late-onset. Under these systems, nonclassic infantile-onset is usually considered a form of late-onset Pompe disease as it doesn’t cause cardiomyopathy in infancy.

Late-onset Pompe disease

When symptoms begin later in life, during childhood or adulthood, the disease is known as late-onset Pompe. This form also may be referred to as juvenile/adult-onset Pompe disease. In people with this form of Pompe disease, GAA enzyme activity has been reported at 40% or less of what is normal.

Muscle weakness, especially in the legs, is a key sign of this type of the disorder. Most patients experience respiratory problems, due to weakness in the muscles used for breathing. Muscle pain or myalgia, fatigue, and exercise intolerance may also occur.

Other possible LOPD manifestations include difficulty rising when sitting, problems with climbing stairs and walking, issues with chewing and swallowing, and an enlarged tongue and liver.

Spinal muscular weakness may lead to scoliosis — a sideways curvature of the spine — and to hyperlordosis, a pronounced inward curving of the lower back.

In general, people whose symptoms appear later in life have less severe manifestations that progress more slowly. Ultimately, the prognosis for people with late-onset Pompe disease depends mainly upon the extent of respiratory muscle involvement.

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