Pompe Disease: Causes, Symptoms, Diagnosis, and Treatment

Pompe disease is a rare, genetically inherited disorder that affects around 1 in 40,000 people in the United States. This condition impairs the ability of muscles to function normally, causing them to weaken over time.  

Pompe disease can be fatal when diagnosed very early in life. Though there is no cure yet, certain treatments and supportive care can help manage the symptoms and improve the quality of life in patients. 

This article discusses everything you should know about this inherited condition, like what it is, why it happens, the different  types and symptoms, and how it is diagnosed and treated.  

What Is Pompe Disease?

Pompe disease, also known as glycogen storage disease type II (GSD2), is a genetic condition that occurs when the body is unable to break down glycogen (a complex sugar) due to the deficiency of a digestive enzyme called acid alpha-glucosidase (GAA). 

Pompe disease is considered a progressive condition, which means symptoms can get worse over time if not treated early.

This condition is also known by other names, such as acid alpha-glucosidase (GAA) deficiency or acid maltase deficiency (acid maltase is another name for acid alpha-glucosidase). 

What Causes Pompe Disease?

Pompe disease is caused by a mutation in the GAA gene, which is responsible for making the acid alpha-glucosidase (GAA) enzyme. Your body uses this enzyme to break down complex sugar (glycogen). 

Typically, the GAA enzyme is present in lysosomes (tiny structures that serve as recycling centers within the cells). Within the lysosomes of the cells, the GAA enzyme helps break down glycogen into glucose, which is the primary source of energy for most of the body’s cells. 

However, in people with Pompe disease, a deficiency or low production of the GAA enzyme due to a mutation in the GAA gene causes glycogen to accumulate within the lysosomes. This buildup damages organs and tissues throughout the body, particularly the muscles, leading to the progressive signs and symptoms of Pompe disease.

Types of Pompe Disease

Pompe disease can affect people at any age, from newborns to adults. This disorder is categorized into two types based on how much enzyme is produced and when the first symptoms appear:

1. Infantile-Onset Pompe Disease (IOPD)

Infantile-onset or early Pompe disease is more severe and progresses more rapidly than late-onset. In patients with this type, the acid alpha-glucosidase enzyme is either produced in very low amounts or not made at all.

Infantile-onset is further divided into two subtypes based on when the symptoms first appear. For instance:

Classic-Infantile Onset

In this type, symptoms start to appear within the first few months of life, most often around 2 – 4 months of age. By the age of 4, muscular damage to the heart develops, causing an enlarged heart (cardiomegaly) and eventually heart failure. 

Moreover, progressive muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects may also occur. Affected infants also fail to gain weight and grow normally. 

Non-Classic Infantile-Onset

Infants tend to show signs of the rare disease by the age of 1. Infants experience progressive muscle weakness and delayed motor skills. The muscle weakness also causes breathing problems in infants with the non-classic type. 

Without treatment, it can be life-threatening within the first year due to respiratory problems.

2. Late-Onset Pompe Disease (LOPD)

LOPD, also known as juvenile or adult Pompe disease, can occur at any age. This type is less severe than infantile-onset. Though LOPD progresses slowly, it can still cause severe disability. 

People with the LOPD type produce a low amount of acid alpha-glucosidase enzyme (GAA), and the first symptoms may typically appear later in childhood, adolescence, or adulthood. 

LOPD patients usually experience progressive muscle weakness (myopathy) that can lead to breathing problems and eventually, respiratory failure. Unlike infantile-onset Pompe disease, this type is less likely to affect the heart. 

What Are the Common Signs and Symptoms?

As discussed earlier, the symptoms of this disease may vary depending on the type and stage of the disease. Some common symptoms include:

• Muscle weakness, especially in the trunk, shoulders, hips, and legs.
• Poor muscle tone (hypotonia), where muscles feel floppy.
• Difficulty breathing due to a weakened diaphragm and respiratory muscles.
• Enlarged heart (more common in the infantile form).
• Feeding problems like difficulty sucking, swallowing, or chewing.
• Delayed motor skills such as rolling over, sitting, or walking.
• Fatigue, such as constant tiredness and low stamina.
• Scoliosis (curvature of the spine due to weakened muscles).

How Is Pompe Disease Diagnosed?

Early and accurate diagnosis is critical, especially if the symptoms of this disorder appear a few months after birth. More definitive and specific tests for Pompe disease include muscle biopsy, blood test, and molecular genetic analysis. 

1. Muscle Biopsy

In Pompe disease, a muscle biopsy often shows muscle fibers with small pockets filled with excess glycogen. 

2. Blood Test

A blood test measures the activity of the acid α-glucosidase (GAA) enzyme using a blood sample or a skin or muscle biopsy sample. Low levels of GAA enzyme in the patient’s blood can help diagnose Pompe disease. 

3. Molecular Genetic Testing

Genetic molecular testing is the second step in confirming the diagnosis of glycogen storage disease type II (GSDII). This helps to identify the mutations in the GAA gene. Currently, over 300 – 500 GAA mutations have been identified, and specific mutations vary between IOPD and LOPD. 

Besides blood tests and genetic analysis, you may also have other laboratory tests to detect or assess the symptoms potentially associated with this disease. This includes:

• Serum Creatine Kinase (CK): To check the level of creatine kinase enzyme in the blood. 
• Electromyography (EMG): This test measures electrical activity in muscles. In other words, it checks how well your muscles work. 
• MRI or CT scans: To check for muscle damage.
• Echocardiogram (Echo) and chest X-rays: To evaluate the heart function and size of the heart, which is enlarged in classic infantile Pompe disease. 
• Pulmonary function tests: Breathing tests that measure lung capacity. If you have adult or juvenile Pompe disease, you may ask to take this test, because respiratory failure is common. 

What Are the Available Treatment Options?

Although there is no cure for Pompe disease, standard treatments like enzyme replacement therapy (ERT) are typically recommended to slow disease progression, improve symptoms, and extend life expectancy in patients. 

1. Enzyme Replacement Therapy (ERT)

ERT is a standard treatment for all patients diagnosed with Pompe disease. In this therapy, recombinant human acid alpha-glucosidase (rhGAA), like Alglucosidase alfa (indicated for IOPD and LOPD) and Avalglucosidase alfa (indicated for LOPD), is administered intravenously to patients. These drugs are genetically engineered enzymes that mimic the function of the normal GAA enzyme and help to:

• Reduce the accumulation of glycogen by breaking it down into simple sugar (glucose).
• Decrease heart size and maintain its normal function.
• Improve muscle function, tone, and strength, or at least slow the progression of the disorder.

Furthermore, in 2023, the FDA approved the combination therapy of cipaglucosidase alfa-atga (Pombiliti) and miglustat (Opfolda) to treat adults with late-onset Pompe disease who weigh ≥40 kg and have symptoms that are not improving on their current enzyme replacement therapy.

2. Additional Treatments

In addition to standard treatment, it is also possible that a treatment team may recommend some supportive therapies, such as:

• Respiratory therapy (if patients have some degree of respiratory failure)
• Physiotherapy (may be used to strengthen respiratory muscles)
• Occupational therapy (to help with daily activities)
• Nutritional therapy (including feeding tubes for infants or dietary adjustments for adults if chewing and swallowing muscles are affected) 

What Is the Life Expectancy of Someone With Pompe Disease?

The outlook for people with this disease depends on the type and how early treatment begins. For instance, babies with infantile-onset often survive less than 2 years due to respiratory or heart failure if not diagnosed and treated earlier. 

With ERT, many children live longer and have improved heart function, though muscle weakness may still progress.

On the other hand, adult-onset Pompe disease progression is slower, and respiratory failure can occur if breathing muscles weaken significantly.

Can We Prevent Pompe Disease?

No, you cannot prevent Pompe disease because it is a genetic condition that is passed down in families in an autosomal recessive pattern, which means you can get this disease if you receive two copies of the mutated GAA from each of your carrier parents. 

Genetic counseling, carrier screening, and prenatal or preimplantation testing can help you understand your risk of having a child with Pompe disease and support informed decision-making.